C-jun: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
'''c-Jun''' is a [[protein]] that in humans is encoded by the '''JUN''' [[gene]].  c-Jun in combination with [[c-Fos]], forms the [[AP-1 transcription factor|AP-1]] early response [[transcription factor]].  It was first identified as the Fos-binding protein '''p39''' and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the [[JNK]] pathway but has also a phosphorylation-independent function. c-jun [[gene knockout|knockout]] is lethal, but [[transgenic animal]]s with a mutated c-jun that cannot be [[phosphorylated]] (termed c-junAA) can survive.
'''c-Jun''' is a [[protein]] that in humans is encoded by the '''JUN''' [[gene]].  c-Jun, in combination with [[c-Fos]], forms the [[AP-1 transcription factor|AP-1]] early response [[transcription factor]].  It was first identified as the Fos-binding protein '''p39''' and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the [[JNK]] pathway but has also a phosphorylation-independent function. c-jun [[gene knockout|knockout]] is lethal, but [[transgenic animal]]s with a mutated c-jun that cannot be [[phosphorylated]] (termed c-junAA) can survive.


This gene is the putative transforming gene of avian sarcoma virus 17. It encodes a protein that is highly similar to the viral protein, and that interacts directly with specific target DNA sequences to regulate [[gene expression]]. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.<ref>{{cite web | title = Entrez Gene: JUN jun oncogene| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3725| accessdate = }}</ref>
This gene is the putative transforming gene of avian sarcoma virus 17. It encodes a protein that is highly similar to the viral protein, and that interacts directly with specific target DNA sequences to regulate [[gene expression]]. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.<ref>{{cite web | title = Entrez Gene: JUN jun oncogene| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3725| access-date = }}</ref>


== Function ==
== Function ==
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Both Jun and its dimerization partners in AP-1 formation are subject to regulation by diverse extracellular stimuli, which include peptide growth factors, pro-inflammatory [[cytokine]]s, oxidative and other forms of cellular stress, and [[UV irradiation]]. For example, UV irradiation is a potent inducer for elevated c-jun  expression.<ref name="Wisdom_1999" />
Both Jun and its dimerization partners in AP-1 formation are subject to regulation by diverse extracellular stimuli, which include peptide growth factors, pro-inflammatory [[cytokine]]s, oxidative and other forms of cellular stress, and [[UV irradiation]]. For example, UV irradiation is a potent inducer for elevated c-jun  expression.<ref name="Wisdom_1999" />


The c-jun transcription is autoregulated by its own product, Jun. The binding of Jun (AP-1) to a high-affinity AP-1 binding site in the jun promoter region induces jun transcription. This positive autoregulation by stimulating its own transcription may be a mechanism for prolonging the signals from extracellular stimuli. This mechanism can have biological significance for the activity of c-jun in cancer.<ref name="pmid3142689">{{cite journal |vauthors=Angel P, Hattori K, Smeal T, Karin M | title = The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1 | journal = Cell | volume = 55 | issue = 5 | pages = 875–85 |date=December 1988 | pmid = 3142689 | doi = 10.1016/0092-8674(88)90143-2 }}</ref>
The c-jun transcription is autoregulated by its own product, Jun. The binding of Jun (AP-1) to a high-affinity AP-1 binding site in the jun promoter region induces jun transcription. This positive autoregulation by stimulating its own transcription may be a mechanism for prolonging the signals from extracellular stimuli. This mechanism can have biological significance for the activity of c-jun in cancer.<ref name="pmid3142689">{{cite journal | vauthors = Angel P, Hattori K, Smeal T, Karin M | title = The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1 | journal = Cell | volume = 55 | issue = 5 | pages = 875–85 | date = December 1988 | pmid = 3142689 | doi = 10.1016/0092-8674(88)90143-2 }}</ref>


Also, the c-jun activities can be regulated by the ERK pathway. Constitutively active ERK is found to increase c-jun transcription and stability through CREB and GSK3. This results in activated c-jun and its downstream targets such as RACK1 and cyclin D1. RACK1 can enhance JNK activity, and activated JNK signaling subsequently exerts regulation on c-jun activity.<ref name="pmid17482134">{{cite journal |vauthors=Lopez-Bergami P, Huang C, Goydos JS, Yip D, Bar-Eli M, Herlyn M, Smalley KS, Mahale A, Eroshkin A, Aaronson S, Ronai Z | title = Rewired ERK-JNK signaling pathways in melanoma | journal = Cancer Cell | volume = 11 | issue = 5 | pages = 447–60 |date=May 2007 | pmid = 17482134 | pmc = 1978100 | doi = 10.1016/j.ccr.2007.03.009 }}</ref>
Also, the c-jun activities can be regulated by the ERK pathway. Constitutively active ERK is found to increase c-jun transcription and stability through CREB and GSK3. This results in activated c-jun and its downstream targets such as RACK1 and cyclin D1. RACK1 can enhance JNK activity, and activated JNK signaling subsequently exerts regulation on c-jun activity.<ref name="pmid17482134">{{cite journal | vauthors = Lopez-Bergami P, Huang C, Goydos JS, Yip D, Bar-Eli M, Herlyn M, Smalley KS, Mahale A, Eroshkin A, Aaronson S, Ronai Z | title = Rewired ERK-JNK signaling pathways in melanoma | journal = Cancer Cell | volume = 11 | issue = 5 | pages = 447–60 | date = May 2007 | pmid = 17482134 | pmc = 1978100 | doi = 10.1016/j.ccr.2007.03.009 }}</ref>


Phosphorylation of Jun at serines 63 and 73 and threonine 91 and 93 increases transcription of the c-jun target genes.<ref name="Nateri_2005">{{cite journal |vauthors=Nateri AS, Spencer-Dene B, Behrens A | title = Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development | journal = Nature | volume = 437 | issue = 7056 | pages = 281–5 |date=September 2005 | pmid = 16007074 | doi = 10.1038/nature03914 |bibcode = 2005Natur.437..281N }}</ref> Therefore, regulation of c-jun activity can be achieved through N-terminal phosphorylation by the Jun N-terminal kinases (JNKs). It is shown that Jun’s activity (AP-1 activity) in stress-induced apoptosis and cellular proliferation is regulated by its N-terminal phosphorylation.<ref name="pmid10080190">{{cite journal |vauthors=Behrens A, Sibilia M, Wagner EF | title = Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation | journal = Nat. Genet. | volume = 21 | issue = 3 | pages = 326–9 |date=March 1999 | pmid = 10080190 | doi = 10.1038/6854 }}</ref>  Another study showed that oncogenic transformation by ras and fos also requires Jun N-terminal phosphorylation at Serine 63 and 73.<ref name="Behrens_2000">{{cite journal |vauthors=Behrens A, Jochum W, Sibilia M, Wagner EF | title = Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation | journal = Oncogene | volume = 19 | issue = 22 | pages = 2657–63 |date=May 2000 | pmid = 10851065 | doi = 10.1038/sj.onc.1203603 }}</ref>
Phosphorylation of Jun at serines 63 and 73 and threonine 91 and 93 increases transcription of the c-jun target genes.<ref name="Nateri_2005">{{cite journal | vauthors = Nateri AS, Spencer-Dene B, Behrens A | title = Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development | journal = Nature | volume = 437 | issue = 7056 | pages = 281–5 | date = September 2005 | pmid = 16007074 | doi = 10.1038/nature03914 | bibcode = 2005Natur.437..281N }}</ref> Therefore, regulation of c-jun activity can be achieved through N-terminal phosphorylation by the Jun N-terminal kinases (JNKs). It is shown that Jun’s activity (AP-1 activity) in stress-induced apoptosis and cellular proliferation is regulated by its N-terminal phosphorylation.<ref name="pmid10080190">{{cite journal | vauthors = Behrens A, Sibilia M, Wagner EF | title = Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation | journal = Nature Genetics | volume = 21 | issue = 3 | pages = 326–9 | date = March 1999 | pmid = 10080190 | doi = 10.1038/6854 }}</ref>  Another study showed that oncogenic transformation by ras and fos also requires Jun N-terminal phosphorylation at Serine 63 and 73.<ref name="Behrens_2000">{{cite journal | vauthors = Behrens A, Jochum W, Sibilia M, Wagner EF | title = Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation | journal = Oncogene | volume = 19 | issue = 22 | pages = 2657–63 | date = May 2000 | pmid = 10851065 | doi = 10.1038/sj.onc.1203603 }}</ref>


===Cell cycle progression===
===Cell cycle progression===
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Studies have shown that c-jun is required for progression through the [[G1 phase]] of the [[cell cycle]], and c-jun null cells show increased G1 arrest. C-jun regulates the transcriptional level of [[cyclin D1]], which is a major [[Rb kinase]]. Rb is a growth suppressor, and it is inactivated by phosphorylation. Therefore, c-jun is required for maintaining sufficient cyclin D1 kinase activity and allowing cell cycle progression.<ref name="Wisdom_1999" />
Studies have shown that c-jun is required for progression through the [[G1 phase]] of the [[cell cycle]], and c-jun null cells show increased G1 arrest. C-jun regulates the transcriptional level of [[cyclin D1]], which is a major [[Rb kinase]]. Rb is a growth suppressor, and it is inactivated by phosphorylation. Therefore, c-jun is required for maintaining sufficient cyclin D1 kinase activity and allowing cell cycle progression.<ref name="Wisdom_1999" />


In cells absent of c-jun, the expression of [[p53]] (cell cycle arrest inducer) and [[p21]] (CDK inhibitor and p53 target gene) is increased, and those cells exhibit cell cycle defect. Overexpression of c-jun in cells results in decreased level of p53 and p21, and exhibits accelerated cell proliferation. C-jun represses p53 transcription by binding to a variant AP-1 site in the p53 promoter. Those results indicate that c-jun downregulates p53 to control cell cycle progression.<ref name="pmid10072388">{{cite journal |vauthors=Schreiber M, Kolbus A, Piu F, Szabowski A, Möhle-Steinlein U, Tian J, Karin M, Angel P, Wagner EF | title = Control of cell cycle progression by c-jun is p53 dependent | journal = Genes Dev. | volume = 13 | issue = 5 | pages = 607–19 |date=March 1999 | pmid = 10072388 | pmc = 316508 | doi =10.1101/gad.13.5.607 }}</ref>
In cells absent of c-jun, the expression of [[p53]] (cell cycle arrest inducer) and [[p21]] (CDK inhibitor and p53 target gene) is increased, and those cells exhibit cell cycle defect. Overexpression of c-jun in cells results in decreased level of p53 and p21, and exhibits accelerated cell proliferation. C-jun represses p53 transcription by binding to a variant AP-1 site in the p53 promoter. Those results indicate that c-jun downregulates p53 to control cell cycle progression.<ref name="pmid10072388">{{cite journal | vauthors = Schreiber M, Kolbus A, Piu F, Szabowski A, Möhle-Steinlein U, Tian J, Karin M, Angel P, Wagner EF | title = Control of cell cycle progression by c-Jun is p53 dependent | journal = Genes & Development | volume = 13 | issue = 5 | pages = 607–19 | date = March 1999 | pmid = 10072388 | pmc = 316508 | doi = 10.1101/gad.13.5.607 }}</ref>


=== Anti-apoptotic activity ===
=== Anti-apoptotic activity ===
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== Clinical significance ==
== Clinical significance ==


It is known that c-jun plays a role in [[cell growth|cellular proliferation]] and apoptosis of the [[endometrium]] throughout the [[menstrual cycle]]. The cyclic change of the c-jun protein levels is significant in the proliferation and apoptosis of glandular epithelial cells. The persistent stromal expression of c-jun protein may prevent [[stromal cell]]s from entering into apoptosis during the late secretory phase.<ref name="pmid14691341">{{cite journal |vauthors=Udou T, Hachisuga T, Tsujioka H, Kawarabayashi T | title = The role of c-jun protein in proliferation and apoptosis of the endometrium throughout the menstrual cycle | journal = Gynecol. Obstet. Invest. | volume = 57 | issue = 3 | pages = 121–6 | year = 2004 | pmid = 14691341 | doi = 10.1159/000075701 }}</ref>
It is known that c-jun plays a role in [[cell growth|cellular proliferation]] and apoptosis of the [[endometrium]] throughout the [[menstrual cycle]]. The cyclic change of the c-jun protein levels is significant in the proliferation and apoptosis of glandular epithelial cells. The persistent stromal expression of c-jun protein may prevent [[stromal cell]]s from entering into apoptosis during the late secretory phase.<ref name="pmid14691341">{{cite journal | vauthors = Udou T, Hachisuga T, Tsujioka H, Kawarabayashi T | title = The role of c-jun protein in proliferation and apoptosis of the endometrium throughout the menstrual cycle | journal = Gynecologic and Obstetric Investigation | volume = 57 | issue = 3 | pages = 121–6 | year = 2004 | pmid = 14691341 | doi = 10.1159/000075701 }}</ref>


=== Cancer ===
=== Cancer ===


C-jun is a proto-oncogene (its protein is Jun) and is the cellular homolog of the viral [[oncoprotein]] v-jun.<ref name="Wisdom_1999">{{cite journal |vauthors=Wisdom R, Johnson RS, Moore C | title = c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms | journal = EMBO J. | volume = 18 | issue = 1 | pages = 188–97 |date=January 1999 | pmid = 9878062 | pmc = 1171114 | doi = 10.1093/emboj/18.1.188 | url = }}</ref>  Jun is the first discovered oncogenic transcription factor.<ref name="pmid12189388">{{cite journal | author = Vogt PK | title = Fortuitous convergences: the beginnings of JUN | journal = Nat. Rev. Cancer | volume = 2 | issue = 6 | pages = 465–9 |date=June 2002 | pmid = 12189388 | doi = 10.1038/nrc818 }}</ref>
C-jun is a proto-oncogene (its protein is Jun) and is the cellular homolog of the viral [[oncoprotein]] v-jun.<ref name="Wisdom_1999">{{cite journal | vauthors = Wisdom R, Johnson RS, Moore C | title = c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms | journal = The EMBO Journal | volume = 18 | issue = 1 | pages = 188–97 | date = January 1999 | pmid = 9878062 | pmc = 1171114 | doi = 10.1093/emboj/18.1.188 }}</ref>  Jun is the first discovered oncogenic transcription factor.<ref name="pmid12189388">{{cite journal | vauthors = Vogt PK | title = Fortuitous convergences: the beginnings of JUN | journal = Nature Reviews. Cancer | volume = 2 | issue = 6 | pages = 465–9 | date = June 2002 | pmid = 12189388 | doi = 10.1038/nrc818 }}</ref>


In a study using [[non-small cell lung cancer]]s (NSCLC), c-jun was found to be overexpressed in 31% of the cases in primary and metastatic lung tumors, whereas normal conducting airway and alveolar epithelia in general did not express c-jun.<ref name="pmid8542585">{{cite journal |vauthors=Szabo E, Riffe ME, Steinberg SM, Birrer MJ, Linnoila RI | title = Altered cJUN expression: an early event in human lung carcinogenesis | journal = Cancer Res. | volume = 56 | issue = 2 | pages = 305–15 |date=January 1996 | pmid = 8542585 | doi = }}</ref>
In a study using [[non-small cell lung cancer]]s (NSCLC), c-jun was found to be overexpressed in 31% of the cases in primary and metastatic lung tumors, whereas normal conducting airway and alveolar epithelia in general did not express c-jun.<ref name="pmid8542585">{{cite journal | vauthors = Szabo E, Riffe ME, Steinberg SM, Birrer MJ, Linnoila RI | title = Altered cJUN expression: an early event in human lung carcinogenesis | journal = Cancer Research | volume = 56 | issue = 2 | pages = 305–15 | date = January 1996 | pmid = 8542585 | doi = }}</ref>


A study with a group consisted of 103 cases of phase I/II invasive breast cancers showed that activated c-jun is expressed predominantly at the invasive front of breast cancer and is associated with proliferation and [[angiogenesis]].<ref name="pmid16733206">{{cite journal |vauthors=Vleugel MM, Greijer AE, Bos R, van der Wall E, van Diest PJ | title = c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer | journal = Hum. Pathol. | volume = 37 | issue = 6 | pages = 668–74 |date=June 2006 | pmid = 16733206 | doi = 10.1016/j.humpath.2006.01.022 }}</ref>
A study with a group consisted of 103 cases of phase I/II invasive breast cancers showed that activated c-jun is expressed predominantly at the invasive front of breast cancer and is associated with proliferation and [[angiogenesis]].<ref name="pmid16733206">{{cite journal | vauthors = Vleugel MM, Greijer AE, Bos R, van der Wall E, van Diest PJ | title = c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer | journal = Human Pathology | volume = 37 | issue = 6 | pages = 668–74 | date = June 2006 | pmid = 16733206 | doi = 10.1016/j.humpath.2006.01.022 }}</ref>


=== Tumor initiation ===
=== Tumor initiation ===


A study was done with liver-specific inactivation of c-jun at different stages of tumor development in mice with chemically induced hepatocellular carcinomas. The result indicates that c-jun is required at the early stage of tumor development, and deletion of c-jun can largely suppress tumor formation. Also, c-jun is required for tumor cell survival between the initiation and progression stages. In contrast to that, inactivation of c-jun in advanced tumors does not impair tumor progression.<ref name="Eferl_2003">{{cite journal |vauthors=Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, Wagner EF | title = Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53 | journal = Cell | volume = 112 | issue = 2 | pages = 181–92 |date=January 2003 | pmid = 12553907 | doi =10.1016/S0092-8674(03)00042-4 }}</ref>
A study was done with liver-specific inactivation of c-jun at different stages of tumor development in mice with chemically induced hepatocellular carcinomas. The result indicates that c-jun is required at the early stage of tumor development, and deletion of c-jun can largely suppress tumor formation. Also, c-jun is required for tumor cell survival between the initiation and progression stages. In contrast to that, inactivation of c-jun in advanced tumors does not impair tumor progression.<ref name="Eferl_2003">{{cite journal | vauthors = Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, Wagner EF | title = Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53 | journal = Cell | volume = 112 | issue = 2 | pages = 181–92 | date = January 2003 | pmid = 12553907 | doi = 10.1016/S0092-8674(03)00042-4 }}</ref>


=== Breast cancer ===
=== Breast cancer ===


Overexpression of c-jun in MCF-7 cells can result in overall increased aggressiveness, as shown by increased cellular motility, increased expression of a matrix-degrading enzyme [[MMP-9]], increased in vitro chemoinvasion, and tumor formation in nude mice in the absence of exogenous [[estrogen]]s. The [[MCF-7]] cells with c-jun overexpression became unresponsive to estrogen and tamoxifen, thus c-jun overexpression is proposed to lead to an estrogen-independent phenotype in breast cancer cells. The observed phenotype for MCF-7 cells with c-jun overexpression is similar to that observed clinically in advanced breast cancer, which had become hormone unresponsive.<ref name="pmid10557095">{{cite journal |vauthors=Smith LM, Wise SC, Hendricks DT, Sabichi AL, Bos T, Reddy P, Brown PH, Birrer MJ | title = cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype | journal = Oncogene | volume = 18 | issue = 44 | pages = 6063–70 |date=October 1999 | pmid = 10557095 | doi = 10.1038/sj.onc.1202989 }}</ref>
Overexpression of c-jun in MCF-7 cells can result in overall increased aggressiveness, as shown by increased cellular motility, increased expression of a matrix-degrading enzyme [[MMP-9]], increased in vitro chemoinvasion, and tumor formation in nude mice in the absence of exogenous [[estrogen]]s. The [[MCF-7]] cells with c-jun overexpression became unresponsive to estrogen and tamoxifen, thus c-jun overexpression is proposed to lead to an estrogen-independent phenotype in breast cancer cells. The observed phenotype for MCF-7 cells with c-jun overexpression is similar to that observed clinically in advanced breast cancer, which had become hormone unresponsive.<ref name="pmid10557095">{{cite journal | vauthors = Smith LM, Wise SC, Hendricks DT, Sabichi AL, Bos T, Reddy P, Brown PH, Birrer MJ | title = cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype | journal = Oncogene | volume = 18 | issue = 44 | pages = 6063–70 | date = October 1999 | pmid = 10557095 | doi = 10.1038/sj.onc.1202989 }}</ref>


The invasive phenotype contributed by c-jun overexpression is confirmed in another study. In addition, this study showed increased in vivo liver metastasis by the breast cancer with c-jun overexpression. This finding suggests that c-jun plays a critical role in the metastasis of breast cancer.<ref name="pmid17672916">{{cite journal |vauthors=Zhang Y, Pu X, Shi M, Chen L, Song Y, Qian L, Yuan G, Zhang H, Yu M, Hu M, Shen B, Guo N | title = Critical role of c-Jun overexpression in liver metastasis of human breast cancer xenograft model | journal = BMC Cancer | volume = 7| pages = 145 | year = 2007 | pmid = 17672916 | pmc = 1959235 | doi = 10.1186/1471-2407-7-145 }}</ref>
The invasive phenotype contributed by c-jun overexpression is confirmed in another study. In addition, this study showed increased in vivo liver metastasis by the breast cancer with c-jun overexpression. This finding suggests that c-jun plays a critical role in the metastasis of breast cancer.<ref name="pmid17672916">{{cite journal | vauthors = Zhang Y, Pu X, Shi M, Chen L, Song Y, Qian L, Yuan G, Zhang H, Yu M, Hu M, Shen B, Guo N | title = Critical role of c-Jun overexpression in liver metastasis of human breast cancer xenograft model | journal = BMC Cancer | volume = 7 | pages = 145 | date = August 2007 | pmid = 17672916 | pmc = 1959235 | doi = 10.1186/1471-2407-7-145 }}</ref>


In mammary tumors, endogenous c-jun was found to play a key role in [[ErbB2]]-induced migration and invasion of mammary epithelial cells. Jun transcriptionally activates the promoters of SCF ([[stem cell factor]]) and [[CCL5]]. The induced SCF and CCL5 expression promotes a self-renewing mammary epithelial population. It suggests that c-jun mediates the expansion of breast cancer stem cells to enhance tumor invasiveness.<ref name="pmid20053993">{{cite journal |vauthors=Jiao X, Katiyar S, Willmarth NE, Liu M, Ma X, Flomenberg N, Lisanti MP, Pestell RG | title = c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion | journal = J. Biol. Chem. | volume = 285 | issue = 11 | pages = 8218–26 |date=March 2010 | pmid = 20053993 | pmc = 2832973 | doi = 10.1074/jbc.M110.100792 }}</ref>
In mammary tumors, endogenous c-jun was found to play a key role in [[ErbB2]]-induced migration and invasion of mammary epithelial cells. Jun transcriptionally activates the promoters of SCF ([[stem cell factor]]) and [[CCL5]]. The induced SCF and CCL5 expression promotes a self-renewing mammary epithelial population. It suggests that c-jun mediates the expansion of breast cancer stem cells to enhance tumor invasiveness.<ref name="pmid20053993">{{cite journal | vauthors = Jiao X, Katiyar S, Willmarth NE, Liu M, Ma X, Flomenberg N, Lisanti MP, Pestell RG | title = c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion | journal = The Journal of Biological Chemistry | volume = 285 | issue = 11 | pages = 8218–26 | date = March 2010 | pmid = 20053993 | pmc = 2832973 | doi = 10.1074/jbc.M110.100792 }}</ref>


=== Cellular differentiation ===
=== Cellular differentiation ===


Ten undifferentiated and highly aggressive sarcomas showed amplification of the jun gene and JUN overexpression at both RNA and protein levels. Overexpression of c-jun in 3T3-L1 cells (a preadipocytic non-tumoral cell line that resembles human [[liposarcoma]]) can block or delay adipocytic differentiation of those cells.<ref name="pmid17418412">{{cite journal |vauthors=Mariani O, Brennetot C, Coindre JM, Gruel N, Ganem C, Delattre O, Stern MH, Aurias A | title = JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas | journal = Cancer Cell | volume = 11 | issue = 4 | pages = 361–74 |date=April 2007 | pmid = 17418412 | doi = 10.1016/j.ccr.2007.02.007 }}</ref>
Ten undifferentiated and highly aggressive sarcomas showed amplification of the jun gene and JUN overexpression at both RNA and protein levels. Overexpression of c-jun in 3T3-L1 cells (a preadipocytic non-tumoral cell line that resembles human [[liposarcoma]]) can block or delay adipocytic differentiation of those cells.<ref name="pmid17418412">{{cite journal | vauthors = Mariani O, Brennetot C, Coindre JM, Gruel N, Ganem C, Delattre O, Stern MH, Aurias A | title = JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas | journal = Cancer Cell | volume = 11 | issue = 4 | pages = 361–74 | date = April 2007 | pmid = 17418412 | doi = 10.1016/j.ccr.2007.02.007 }}</ref>
 
=== Nerve and Spinal Cord Regeneration ===
Peripheral nerve injury in rodents rapidly activates JNK signaling which in turn activates c-Jun. In contrast, nerve injury in the central nervous system does not. c-Jun is sufficient to promote axon regeneration in both the peripheral and central nervous systems as overexpression in both dorsal root ganglion neurons and cortical neurons leads to increased regeneration. <ref>{{cite journal | vauthors = Mahar M, Cavalli V | title = Intrinsic mechanisms of neuronal axon regeneration | language = En | journal = Nature Reviews. Neuroscience | volume = 19 | issue = 6 | pages = 323–337 | date = June 2018 | pmid = 29666508 | pmc = 5987780 | doi = 10.1038/s41583-018-0001-8 | url = http://www.nature.com/articles/s41583-018-0001-8 }}</ref>


== As anti-cancer drug target ==
== As anti-cancer drug target ==
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A study showed that oncogenic transformation by ras and fos requires Jun N-terminal phosphorylation at Serine 63 and 73 by the Jun N- terminal kinases (JNK). In this study, the induced skin tumor and osteosarcoma showed impaired development in mice with a mutant Jun incapable of N-terminal phosphorylation.<ref name= "Behrens_2000" />  Also, in a mouse model of intestinal cancer, genetic abrogation of Jun N-terminal phosphorylation or gut-specific c-jun inactivation attenuated cancer development and prolonged lifespan.<ref name= "Nateri_2005" /> Therefore, targeting the N-terminal phosphorylation of Jun (or the JNK signaling pathway) can be a potential strategy for inhibiting tumor growth.
A study showed that oncogenic transformation by ras and fos requires Jun N-terminal phosphorylation at Serine 63 and 73 by the Jun N- terminal kinases (JNK). In this study, the induced skin tumor and osteosarcoma showed impaired development in mice with a mutant Jun incapable of N-terminal phosphorylation.<ref name= "Behrens_2000" />  Also, in a mouse model of intestinal cancer, genetic abrogation of Jun N-terminal phosphorylation or gut-specific c-jun inactivation attenuated cancer development and prolonged lifespan.<ref name= "Nateri_2005" /> Therefore, targeting the N-terminal phosphorylation of Jun (or the JNK signaling pathway) can be a potential strategy for inhibiting tumor growth.


In melanoma-derived B16-F10 cancer cells, c-jun inactivation by a pharmacological JNK/jun inhibitor SP combined with JunB knockdown can result in cytotoxic effect, leading to cell arrest and apoptosis. This anti-JunB /Jun strategy can increase the survival of mice inoculated with tumor cells, which suggests a potential antitumor strategy through Jun and JunB inhibition.<ref name="pmid17667939">{{cite journal |vauthors=Gurzov EN, Bakiri L, Alfaro JM, Wagner EF, Izquierdo M | title = Targeting Jun and JunB proteins as potential anticancer cell therapy | journal = Oncogene | volume = 27 | issue = 5 | pages = 641–52 |date=January 2008 | pmid = 17667939 | doi = 10.1038/sj.onc.1210690 }}</ref>
In melanoma-derived B16-F10 cancer cells, c-jun inactivation by a pharmacological JNK/jun inhibitor SP combined with JunB knockdown can result in cytotoxic effect, leading to cell arrest and apoptosis. This anti-JunB /Jun strategy can increase the survival of mice inoculated with tumor cells, which suggests a potential antitumor strategy through Jun and JunB inhibition.<ref name="pmid17667939">{{cite journal | vauthors = Gurzov EN, Bakiri L, Alfaro JM, Wagner EF, Izquierdo M | title = Targeting c-Jun and JunB proteins as potential anticancer cell therapy | journal = Oncogene | volume = 27 | issue = 5 | pages = 641–52 | date = January 2008 | pmid = 17667939 | doi = 10.1038/sj.onc.1210690 }}</ref>


==Anti-cancer property of c-jun==
==Anti-cancer property of c-jun==
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=== p16INK4a ===
=== p16INK4a ===
p16INK4a is a tumor suppressor and a cell cycle inhibitor, and a study shows that c-jun acts as “bodyguard” to p16INK4a by preventing methylation of the p16INK4a promoter. Therefore, c-jun can prevent silencing of the gene p16INK4a.<ref name="pmid21789792">{{cite journal |vauthors=Kollmann K, Heller G, Sexl V | title = c-JUN prevents methylation of p16(INK4a) (and Cdk6): the villain turned bodyguard | journal = Oncotarget | volume = 2 | issue = 5 | pages = 422–7 |date=May 2011 | pmid = 21789792 | pmc = 3248190 | doi = 10.18632/oncotarget.279}}</ref>
p16INK4a is a tumor suppressor and a cell cycle inhibitor, and a study shows that c-jun acts as “bodyguard” to p16INK4a by preventing methylation of the p16INK4a promoter. Therefore, c-jun can prevent silencing of the gene p16INK4a.<ref name="pmid21789792">{{cite journal | vauthors = Kollmann K, Heller G, Sexl V | title = c-JUN prevents methylation of p16(INK4a) (and Cdk6): the villain turned bodyguard | journal = Oncotarget | volume = 2 | issue = 5 | pages = 422–7 | date = May 2011 | pmid = 21789792 | pmc = 3248190 | doi = 10.18632/oncotarget.279 }}</ref>


=== Tylophorine ===
=== Tylophorine ===
Tylophorine is a type of plant-derived alkaloid with anticancer activity by inducing cell cycle arrest. A study demonstrated that tylophorine treatment increased c-jun protein accumulation. Then c-jun expression in conjunction with tylophorine promotes G1 arrest in carcinoma cells through the downregulation of cyclin A2. Therefore, the result indicates that the anticancer mechanism of tylophorine is mediated through c-jun.<ref name="pmid23385061">{{cite journal |vauthors=Yang CW, Lee YZ, Hsu HY, Wu CM, Chang HY, Chao YS, Lee SJ | title = c-Jun-mediated anticancer mechanisms of tylophorine | journal = Carcinogenesis | volume = 34| issue = 6| pages = 1304–14|date=March 2013 | pmid = 23385061 | doi = 10.1093/carcin/bgt039 }}</ref>
Tylophorine is a type of plant-derived alkaloid with anticancer activity by inducing cell cycle arrest. A study demonstrated that tylophorine treatment increased c-jun protein accumulation. Then c-jun expression in conjunction with tylophorine promotes G1 arrest in carcinoma cells through the downregulation of cyclin A2. Therefore, the result indicates that the anticancer mechanism of tylophorine is mediated through c-jun.<ref name="pmid23385061">{{cite journal | vauthors = Yang CW, Lee YZ, Hsu HY, Wu CM, Chang HY, Chao YS, Lee SJ | title = c-Jun-mediated anticancer mechanisms of tylophorine | journal = Carcinogenesis | volume = 34 | issue = 6 | pages = 1304–14 | date = June 2013 | pmid = 23385061 | doi = 10.1093/carcin/bgt039 |authorlink5=Howard Y. Chang}}</ref>


== Interactions ==
== Interactions ==
C-jun has been shown to [[Protein-protein interaction|interact]] with:
C-jun has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[Activating transcription factor 2|ATF2]]<ref name = pmid8027667>{{cite journal |vauthors=Newell CL, Deisseroth AB, Lopez-Berestein G | title = Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene | volume = 56 | issue = 1 | pages = 27–35 | year = 1994 | pmid = 8027667 | doi = | journal = Journal of leukocyte biology }}</ref><ref name = pmid2320002>{{cite journal |vauthors=Kara CJ, Liou HC, Ivashkiv LB, Glimcher LH | title = A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain | volume = 10 | issue = 4 | pages = 1347–57 | year = 1990 | pmid = 2320002 | pmc = 362236 | doi = | journal = Molecular and Cellular Biology }}</ref><ref name = pmid1827203>{{cite journal |vauthors=Hai T, Curran T | title = Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity | volume = 88 | issue = 9 | pages = 3720–4 | year = 1991 | pmid = 1827203 | pmc = 51524 | doi = 10.1073/pnas.88.9.3720| journal = Proceedings of the National Academy of Sciences of the United States of America |bibcode = 1991PNAS...88.3720H }}</ref>  
* [[Activating transcription factor 2|ATF2]]<ref name = pmid8027667>{{cite journal | vauthors = Newell CL, Deisseroth AB, Lopez-Berestein G | title = Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene | journal = Journal of Leukocyte Biology | volume = 56 | issue = 1 | pages = 27–35 | date = July 1994 | pmid = 8027667 | doi = }}</ref><ref name = pmid2320002>{{cite journal | vauthors = Kara CJ, Liou HC, Ivashkiv LB, Glimcher LH | title = A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain | journal = Molecular and Cellular Biology | volume = 10 | issue = 4 | pages = 1347–57 | date = April 1990 | pmid = 2320002 | pmc = 362236 | doi = }}</ref><ref name = pmid1827203>{{cite journal | vauthors = Hai T, Curran T | title = Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 9 | pages = 3720–4 | date = May 1991 | pmid = 1827203 | pmc = 51524 | doi = 10.1073/pnas.88.9.3720 | bibcode = 1991PNAS...88.3720H }}</ref>  
* [[Androgen receptor|AR]]<ref name = pmid9211894>{{cite journal |vauthors=Sato N, Sadar MD, Bruchovsky N, Saatcioglu F, Rennie PS, Sato S, Lange PH, Gleave ME | title = Androgenic induction of prostate-specific antigen gene is repressed by protein-protein interaction between the androgen receptor and AP-1/c-Jun in the human prostate cancer cell line LNCaP | volume = 272 | issue = 28 | pages = 17485–94 | year = 1997 | pmid = 9211894 | doi = 10.1074/jbc.272.28.17485| journal = The Journal of Biological Chemistry }}</ref>  
* [[Androgen receptor|AR]]<ref name = pmid9211894>{{cite journal | vauthors = Sato N, Sadar MD, Bruchovsky N, Saatcioglu F, Rennie PS, Sato S, Lange PH, Gleave ME | title = Androgenic induction of prostate-specific antigen gene is repressed by protein-protein interaction between the androgen receptor and AP-1/c-Jun in the human prostate cancer cell line LNCaP | journal = The Journal of Biological Chemistry | volume = 272 | issue = 28 | pages = 17485–94 | date = July 1997 | pmid = 9211894 | doi = 10.1074/jbc.272.28.17485 }}</ref>  
* [[ASCC3]]<ref name = pmid12077347>{{cite journal |vauthors=Jung DJ, Sung HS, Goo YW, Lee HM, Park OK, Jung SY, Lim J, Kim HJ, Lee SK, Kim TS, Lee JW, Lee YC | title = Novel transcription coactivator complex containing activating signal cointegrator 1 | volume = 22 | issue = 14 | pages = 5203–11 | year = 2002 | pmid = 12077347 | pmc = 139772 | doi =10.1128/MCB.22.14.5203-5211.2002 | journal = Molecular and Cellular Biology }}</ref>  
* [[ASCC3]]<ref name = pmid12077347>{{cite journal | vauthors = Jung DJ, Sung HS, Goo YW, Lee HM, Park OK, Jung SY, Lim J, Kim HJ, Lee SK, Kim TS, Lee JW, Lee YC | title = Novel transcription coactivator complex containing activating signal cointegrator 1 | journal = Molecular and Cellular Biology | volume = 22 | issue = 14 | pages = 5203–11 | date = July 2002 | pmid = 12077347 | pmc = 139772 | doi = 10.1128/MCB.22.14.5203-5211.2002 }}</ref>  
* [[ATF3]]<ref name = pmid1827203/><ref name = pmid14667575>{{cite journal |vauthors=Pearson AG, Gray CW, Pearson JF, Greenwood JM, During MJ, Dragunow M | title = ATF3 enhances c-Jun-mediated neurite sprouting | volume = 120 | issue = 1 | pages = 38–45 | year = 2003 | pmid = 14667575 | doi = 10.1016/j.molbrainres.2003.09.014| journal = Brain research. Molecular brain research }}</ref><ref name = pmid8622660>{{cite journal |vauthors=Chen BP, Wolfgang CD, Hai T | title = Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10 | volume = 16 | issue = 3 | pages = 1157–68 | year = 1996 | pmid = 8622660 | pmc = 231098 | doi = 10.1128/MCB.16.3.1157| journal = Molecular and Cellular Biology }}</ref>  
* [[ATF3]]<ref name = pmid1827203/><ref name = pmid14667575>{{cite journal | vauthors = Pearson AG, Gray CW, Pearson JF, Greenwood JM, During MJ, Dragunow M | title = ATF3 enhances c-Jun-mediated neurite sprouting | journal = Brain Research. Molecular Brain Research | volume = 120 | issue = 1 | pages = 38–45 | date = December 2003 | pmid = 14667575 | doi = 10.1016/j.molbrainres.2003.09.014 }}</ref><ref name = pmid8622660>{{cite journal | vauthors = Chen BP, Wolfgang CD, Hai T | title = Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10 | journal = Molecular and Cellular Biology | volume = 16 | issue = 3 | pages = 1157–68 | date = March 1996 | pmid = 8622660 | pmc = 231098 | doi = 10.1128/MCB.16.3.1157 }}</ref>  
* [[BCL3]]<ref name = pmid10497212>{{cite journal |vauthors=Na SY, Choi JE, Kim HJ, Jhun BH, Lee YC, Lee JW | title = Bcl3, an IkappaB protein, stimulates activating protein-1 transactivation and cellular proliferation | volume = 274 | issue = 40 | pages = 28491–6 | year = 1999 | pmid = 10497212 | doi = 10.1074/jbc.274.40.28491| journal = The Journal of Biological Chemistry }}</ref>  
* [[BCL3]]<ref name = pmid10497212>{{cite journal | vauthors = Na SY, Choi JE, Kim HJ, Jhun BH, Lee YC, Lee JW | title = Bcl3, an IkappaB protein, stimulates activating protein-1 transactivation and cellular proliferation | journal = The Journal of Biological Chemistry | volume = 274 | issue = 40 | pages = 28491–6 | date = October 1999 | pmid = 10497212 | doi = 10.1074/jbc.274.40.28491 }}</ref>  
* [[BCL6]]<ref name = pmid12165517>{{cite journal |vauthors=Vasanwala FH, Kusam S, Toney LM, Dent AL | title = Repression of AP-1 function: a mechanism for the regulation of Blimp-1 expression and B lymphocyte differentiation by the B cell lymphoma-6 protooncogene | volume = 169 | issue = 4 | pages = 1922–9 | year = 2002 | pmid = 12165517 | doi = 10.4049/jimmunol.169.4.1922| journal = Journal of Immunology }}</ref>  
* [[BCL6]]<ref name = pmid12165517>{{cite journal | vauthors = Vasanwala FH, Kusam S, Toney LM, Dent AL | title = Repression of AP-1 function: a mechanism for the regulation of Blimp-1 expression and B lymphocyte differentiation by the B cell lymphoma-6 protooncogene | journal = Journal of Immunology | volume = 169 | issue = 4 | pages = 1922–9 | date = August 2002 | pmid = 12165517 | doi = 10.4049/jimmunol.169.4.1922 }}</ref>  
* [[BRCA1]]<ref name = pmid12080089>{{cite journal |vauthors=Hu YF, Li R | title = JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction | volume = 16 | issue = 12 | pages = 1509–17 | year = 2002 | pmid = 12080089 | pmc = 186344 | doi = 10.1101/gad.995502 | journal = Genes & Development }}</ref>  
* [[BRCA1]]<ref name = pmid12080089>{{cite journal | vauthors = Hu YF, Li R | title = JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction | journal = Genes & Development | volume = 16 | issue = 12 | pages = 1509–17 | date = June 2002 | pmid = 12080089 | pmc = 186344 | doi = 10.1101/gad.995502 }}</ref>  
* [[C-Fos]]<ref name = pmid11053448>{{cite journal |vauthors=Ito T, Yamauchi M, Nishina M, Yamamichi N, Mizutani T, Ui M, Murakami M, Iba H | title = Identification of SWI.SNF complex subunit BAF60a as a determinant of the transactivation potential of Fos/Jun dimers | volume = 276 | issue = 4 | pages = 2852–7 | year = 2001 | pmid = 11053448 | doi = 10.1074/jbc.M009633200 | journal = Journal of Biological Chemistry }}</ref><ref name = pmid9160889>{{cite journal |vauthors=Pognonec P, Boulukos KE, Aperlo C, Fujimoto M, Ariga H, Nomoto A, Kato H | title = Cross-family interaction between the bHLHZip USF and bZip Fra1 proteins results in down-regulation of AP1 activity | volume = 14 | issue = 17 | pages = 2091–8 | year = 1997 | pmid = 9160889 | doi = 10.1038/sj.onc.1201046 | journal = Oncogene }}</ref><ref name = pmid7816143>{{cite journal |vauthors=Glover JN, Harrison SC | title = Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA | volume = 373 | issue = 6511 | pages = 257–61 | year = 1995 | pmid = 7816143 | doi = 10.1038/373257a0 | journal = Nature |bibcode = 1995Natur.373..257G }}</ref><ref name = pmid10488148>{{cite journal |vauthors=Yang X, Chen Y, Gabuzda D | title = ERK MAP kinase links cytokine signals to activation of latent HIV-1 infection by stimulating a cooperative interaction of AP-1 and NF-kappaB | volume = 274 | issue = 39 | pages = 27981–8 | year = 1999 | pmid = 10488148 | doi = 10.1074/jbc.274.39.27981| journal = The Journal of Biological Chemistry }}</ref><ref name = pmid8440710>{{cite journal |vauthors=Nomura N, Zu YL, Maekawa T, Tabata S, Akiyama T, Ishii S | title = Isolation and characterization of a novel member of the gene family encoding the cAMP response element-binding protein CRE-BP1 | volume = 268 | issue = 6 | pages = 4259–66 | year = 1993 | pmid = 8440710 | doi = | journal = The Journal of Biological Chemistry }}</ref><ref name = pmid8380166>{{cite journal |vauthors=Finkel T, Duc J, Fearon ER, Dang CV, Tomaselli GF | title = Detection and modulation in vivo of helix-loop-helix protein-protein interactions | volume = 268 | issue = 1 | pages = 5–8 | year = 1993 | pmid = 8380166 | doi = | journal = The Journal of Biological Chemistry }}</ref><ref name = pmid9872330>{{cite journal |vauthors=Venugopal R, Jaiswal AK | title = Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes | volume = 17 | issue = 24 | pages = 3145–56 | year = 1998 | pmid = 9872330 | doi = 10.1038/sj.onc.1202237 | journal = Oncogene }}</ref>  
* [[C-Fos]]<ref name = pmid11053448>{{cite journal | vauthors = Ito T, Yamauchi M, Nishina M, Yamamichi N, Mizutani T, Ui M, Murakami M, Iba H | title = Identification of SWI.SNF complex subunit BAF60a as a determinant of the transactivation potential of Fos/Jun dimers | journal = The Journal of Biological Chemistry | volume = 276 | issue = 4 | pages = 2852–7 | date = January 2001 | pmid = 11053448 | doi = 10.1074/jbc.M009633200 }}</ref><ref name = pmid9160889>{{cite journal | vauthors = Pognonec P, Boulukos KE, Aperlo C, Fujimoto M, Ariga H, Nomoto A, Kato H | title = Cross-family interaction between the bHLHZip USF and bZip Fra1 proteins results in down-regulation of AP1 activity | journal = Oncogene | volume = 14 | issue = 17 | pages = 2091–8 | date = May 1997 | pmid = 9160889 | doi = 10.1038/sj.onc.1201046 }}</ref><ref name = pmid7816143>{{cite journal | vauthors = Glover JN, Harrison SC | title = Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA | journal = Nature | volume = 373 | issue = 6511 | pages = 257–61 | date = January 1995 | pmid = 7816143 | doi = 10.1038/373257a0 | bibcode = 1995Natur.373..257G }}</ref><ref name = pmid10488148>{{cite journal | vauthors = Yang X, Chen Y, Gabuzda D | title = ERK MAP kinase links cytokine signals to activation of latent HIV-1 infection by stimulating a cooperative interaction of AP-1 and NF-kappaB | journal = The Journal of Biological Chemistry | volume = 274 | issue = 39 | pages = 27981–8 | date = September 1999 | pmid = 10488148 | doi = 10.1074/jbc.274.39.27981 }}</ref><ref name = pmid8440710>{{cite journal | vauthors = Nomura N, Zu YL, Maekawa T, Tabata S, Akiyama T, Ishii S | title = Isolation and characterization of a novel member of the gene family encoding the cAMP response element-binding protein CRE-BP1 | journal = The Journal of Biological Chemistry | volume = 268 | issue = 6 | pages = 4259–66 | date = February 1993 | pmid = 8440710 | doi = }}</ref><ref name = pmid8380166>{{cite journal | vauthors = Finkel T, Duc J, Fearon ER, Dang CV, Tomaselli GF | title = Detection and modulation in vivo of helix-loop-helix protein-protein interactions | journal = The Journal of Biological Chemistry | volume = 268 | issue = 1 | pages = 5–8 | date = January 1993 | pmid = 8380166 | doi = }}</ref><ref name = pmid9872330>{{cite journal | vauthors = Venugopal R, Jaiswal AK | title = Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes | journal = Oncogene | volume = 17 | issue = 24 | pages = 3145–56 | date = December 1998 | pmid = 9872330 | doi = 10.1038/sj.onc.1202237 }}</ref>  
* [[Casein kinase 2, alpha 1|CSNK2A1]]<ref name = pmid9685505/>  
* [[Casein kinase 2, alpha 1|CSNK2A1]]<ref name = pmid9685505/>  
* [[Cofactor of BRCA1|NELFB]]<ref name = pmid15530430>{{cite journal |vauthors=Zhong H, Zhu J, Zhang H, Ding L, Sun Y, Huang C, Ye Q | title = COBRA1 inhibits AP-1 transcriptional activity in transfected cells | volume = 325 | issue = 2 | pages = 568–73 | year = 2004 | pmid = 15530430 | doi = 10.1016/j.bbrc.2004.10.079 | journal = Biochemical and Biophysical Research Communications }}</ref>  
* [[Cofactor of BRCA1|NELFB]]<ref name = pmid15530430>{{cite journal | vauthors = Zhong H, Zhu J, Zhang H, Ding L, Sun Y, Huang C, Ye Q | title = COBRA1 inhibits AP-1 transcriptional activity in transfected cells | journal = Biochemical and Biophysical Research Communications | volume = 325 | issue = 2 | pages = 568–73 | date = December 2004 | pmid = 15530430 | doi = 10.1016/j.bbrc.2004.10.079 }}</ref>  
* [[COP9 constitutive photomorphogenic homolog subunit 5|COPS5]]<ref name = pmid8837781>{{cite journal |vauthors=Claret FX, Hibi M, Dhut S, Toda T, Karin M | title = A new group of conserved coactivators that increase the specificity of AP-1 transcription factors | volume = 383 | issue = 6599 | pages = 453–7 | year = 1996 | pmid = 8837781 | doi = 10.1038/383453a0 | journal = Nature |bibcode = 1996Natur.383..453C }}</ref>  
* [[COP9 constitutive photomorphogenic homolog subunit 5|COPS5]]<ref name = pmid8837781>{{cite journal | vauthors = Claret FX, Hibi M, Dhut S, Toda T, Karin M | title = A new group of conserved coactivators that increase the specificity of AP-1 transcription factors | journal = Nature | volume = 383 | issue = 6599 | pages = 453–7 | date = October 1996 | pmid = 8837781 | doi = 10.1038/383453a0 | bibcode = 1996Natur.383..453C }}</ref>  
* [[CREB binding protein|CREBBP]]<ref name = pmid9786917>{{cite journal |vauthors=Sano Y, Tokitou F, Dai P, Maekawa T, Yamamoto T, Ishii S | title = CBP alleviates the intramolecular inhibition of ATF-2 function | volume = 273 | issue = 44 | pages = 29098–105 | year = 1998 | pmid = 9786917 | doi = 10.1074/jbc.273.44.29098| journal = The Journal of Biological Chemistry }}</ref>  
* [[CREB binding protein|CREBBP]]<ref name = pmid9786917>{{cite journal | vauthors = Sano Y, Tokitou F, Dai P, Maekawa T, Yamamoto T, Ishii S | title = CBP alleviates the intramolecular inhibition of ATF-2 function | journal = The Journal of Biological Chemistry | volume = 273 | issue = 44 | pages = 29098–105 | date = October 1998 | pmid = 9786917 | doi = 10.1074/jbc.273.44.29098 }}</ref>  
* [[CSNK2A2]]<ref name = pmid9685505>{{cite journal |vauthors=Yamaguchi Y, Wada T, Suzuki F, Takagi T, Hasegawa J, Handa H | title = Casein kinase II interacts with the bZIP domains of several transcription factors | volume = 26 | issue = 16 | pages = 3854–61 | year = 1998 | pmid = 9685505 | pmc = 147779 | doi = 10.1093/nar/26.16.3854| journal = Nucleic Acids Research }}</ref>  
* [[CSNK2A2]]<ref name = pmid9685505>{{cite journal | vauthors = Yamaguchi Y, Wada T, Suzuki F, Takagi T, Hasegawa J, Handa H | title = Casein kinase II interacts with the bZIP domains of several transcription factors | journal = Nucleic Acids Research | volume = 26 | issue = 16 | pages = 3854–61 | date = August 1998 | pmid = 9685505 | pmc = 147779 | doi = 10.1093/nar/26.16.3854 }}</ref>  
* [[DDX21]],<ref name = pmid11823437>{{cite journal |vauthors=Westermarck J, Weiss C, Saffrich R, Kast J, Musti AM, Wessely M, Ansorge W, Séraphin B, Wilm M, Valdez BC, Bohmann D | title = The DEXD/H-box RNA helicase RHII/Gu is a co-factor for c-Jun-activated transcription | volume = 21 | issue = 3 | pages = 451–60 | year = 2002 | pmid = 11823437 | pmc = 125820 | doi =10.1093/emboj/21.3.451 | journal = The EMBO Journal }}</ref>  
* [[DDX21]],<ref name = pmid11823437>{{cite journal | vauthors = Westermarck J, Weiss C, Saffrich R, Kast J, Musti AM, Wessely M, Ansorge W, Séraphin B, Wilm M, Valdez BC, Bohmann D | title = The DEXD/H-box RNA helicase RHII/Gu is a co-factor for c-Jun-activated transcription | journal = The EMBO Journal | volume = 21 | issue = 3 | pages = 451–60 | date = February 2002 | pmid = 11823437 | pmc = 125820 | doi = 10.1093/emboj/21.3.451 }}</ref>  
* [[DNA damage-inducible transcript 3|DDIT3]]<ref name = pmid10523647>{{cite journal |vauthors=Ubeda M, Vallejo M, Habener JF | title = CHOP enhancement of gene transcription by interactions with Jun/Fos AP-1 complex proteins | volume = 19 | issue = 11 | pages = 7589–99 | year = 1999 | pmid = 10523647 | pmc = 84780 | doi = | journal = Molecular and Cellular Biology }}</ref>  
* [[DNA damage-inducible transcript 3|DDIT3]]<ref name = pmid10523647>{{cite journal | vauthors = Ubeda M, Vallejo M, Habener JF | title = CHOP enhancement of gene transcription by interactions with Jun/Fos AP-1 complex proteins | journal = Molecular and Cellular Biology | volume = 19 | issue = 11 | pages = 7589–99 | date = November 1999 | pmid = 10523647 | pmc = 84780 | doi = }}</ref>  
* [[ERG (gene)|ERG]]<ref name = pmid11278640>{{cite journal |vauthors=Verger A, Buisine E, Carrère S, Wintjens R, Flourens A, Coll J, Stéhelin D, Duterque-Coquillaud M | title = Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation | volume = 276 | issue = 20 | pages = 17181–9 | year = 2001 | pmid = 11278640 | doi = 10.1074/jbc.M010208200 | journal = Journal of Biological Chemistry }}</ref>  
* [[ERG (gene)|ERG]]<ref name = pmid11278640>{{cite journal | vauthors = Verger A, Buisine E, Carrère S, Wintjens R, Flourens A, Coll J, Stéhelin D, Duterque-Coquillaud M | title = Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 20 | pages = 17181–9 | date = May 2001 | pmid = 11278640 | doi = 10.1074/jbc.M010208200 }}</ref>  
* [[ETS2]],<ref name = pmid9334186>{{cite journal |vauthors=Basuyaux JP, Ferreira E, Stéhelin D, Butticè G | title = The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner | volume = 272 | issue = 42 | pages = 26188–95 | year = 1997 | pmid = 9334186 | doi = 10.1074/jbc.272.42.26188| journal = The Journal of Biological Chemistry }}</ref>  
* [[ETS2]],<ref name = pmid9334186>{{cite journal | vauthors = Basuyaux JP, Ferreira E, Stéhelin D, Butticè G | title = The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner | journal = The Journal of Biological Chemistry | volume = 272 | issue = 42 | pages = 26188–95 | date = October 1997 | pmid = 9334186 | doi = 10.1074/jbc.272.42.26188 }}</ref>  
* [[FOSL1]]<ref name = pmid9160889/>  
* [[FOSL1]]<ref name = pmid9160889/>  
* [[Homeobox protein TGIF1|TGIF1]]<ref name = pmid11371641>{{cite journal |vauthors=Pessah M, Prunier C, Marais J, Ferrand N, Mazars A, Lallemand F, Gauthier JM, Atfi A | title = c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity | volume = 98 | issue = 11 | pages = 6198–203 | year = 2001 | pmid = 11371641 | pmc = 33445 | doi = 10.1073/pnas.101579798 | journal = Proceedings of the National Academy of Sciences |bibcode = 2001PNAS...98.6198P }}</ref>  
* [[Homeobox protein TGIF1|TGIF1]]<ref name = pmid11371641>{{cite journal | vauthors = Pessah M, Prunier C, Marais J, Ferrand N, Mazars A, Lallemand F, Gauthier JM, Atfi A | title = c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 11 | pages = 6198–203 | date = May 2001 | pmid = 11371641 | pmc = 33445 | doi = 10.1073/pnas.101579798 | bibcode = 2001PNAS...98.6198P }}</ref>  
* [[MAPK8]]<ref name = pmid14633987>{{cite journal |vauthors=Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K | title = Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling | volume = 22 | issue = 23 | pages = 6277–88 | year = 2003 | pmid = 14633987 | pmc = 291846 | doi = 10.1093/emboj/cdg605 | journal = The EMBO Journal }}</ref><ref name = pmid9774977>{{cite journal |vauthors=Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H | title = ASK1 is essential for JNK/SAPK activation by TRAF2 | volume = 2 | issue = 3 | pages = 389–95 | year = 1998 | pmid = 9774977 | doi = 10.1016/S1097-2765(00)80283-X| journal = Molecular Cell }}</ref><ref name = pmid8137421>{{cite journal |vauthors=Dérijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ | title = JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain | volume = 76 | issue = 6 | pages = 1025–37 | year = 1994 | pmid = 8137421 | doi = 10.1016/0092-8674(94)90380-8| journal = Cell }}</ref><ref name = pmid12052834>{{cite journal |vauthors=Yazgan O, Pfarr CM | title = Regulation of two JunD isoforms by Jun N-terminal kinases | volume = 277 | issue = 33 | pages = 29710–8 | year = 2002 | pmid = 12052834 | doi = 10.1074/jbc.M204552200 | journal = Journal of Biological Chemistry }}</ref><ref name = pmid11479302>{{cite journal |vauthors=Tada K, Okazaki T, Sakon S, Kobarai T, Kurosawa K, Yamaoka S, Hashimoto H, Mak TW, Yagita H, Okumura K, Yeh WC, Nakano H | title = Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death | volume = 276 | issue = 39 | pages = 36530–4 | year = 2001 | pmid = 11479302 | doi = 10.1074/jbc.M104837200 | journal = Journal of Biological Chemistry }}</ref><ref name = pmid8621542>{{cite journal |vauthors=Meyer CF, Wang X, Chang C, Templeton D, Tan TH | title = Interaction between c-Rel and the mitogen-activated protein kinase kinase kinase 1 signaling cascade in mediating kappaB enhancer activation | volume = 271 | issue = 15 | pages = 8971–6 | year = 1996 | pmid = 8621542 | doi = 10.1074/jbc.271.15.8971| journal = The Journal of Biological Chemistry }}</ref><ref name = pmid8586671>{{cite journal |vauthors=Cano E, Hazzalin CA, Kardalinou E, Buckle RS, Mahadevan LC | title = Neither ERK nor JNK/SAPK MAP kinase subtypes are essential for histone H3/HMG-14 phosphorylation or c-fos and c-jun induction | volume = 108 | issue = 11| pages = 3599–609 | year = 1995 | pmid = 8586671 | doi = | journal = Journal of Cell Science }}</ref><ref name = pmid9207092>{{cite journal |vauthors=Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T, Davis RJ | title = Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase | volume = 94 | issue = 14 | pages = 7337–42 | year = 1997 | pmid = 9207092 | pmc = 23822 | doi =10.1073/pnas.94.14.7337 | bibcode = 1997PNAS...94.7337T | journal = Proceedings of the National Academy of Sciences of the United States of America }}</ref>  
* [[MAPK8]]<ref name = pmid14633987>{{cite journal | vauthors = Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K | title = Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling | journal = The EMBO Journal | volume = 22 | issue = 23 | pages = 6277–88 | date = December 2003 | pmid = 14633987 | pmc = 291846 | doi = 10.1093/emboj/cdg605 }}</ref><ref name = pmid9774977>{{cite journal | vauthors = Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H | title = ASK1 is essential for JNK/SAPK activation by TRAF2 | journal = Molecular Cell | volume = 2 | issue = 3 | pages = 389–95 | date = September 1998 | pmid = 9774977 | doi = 10.1016/S1097-2765(00)80283-X }}</ref><ref name = pmid8137421>{{cite journal | vauthors = Dérijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ | title = JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain | journal = Cell | volume = 76 | issue = 6 | pages = 1025–37 | date = March 1994 | pmid = 8137421 | doi = 10.1016/0092-8674(94)90380-8 }}</ref><ref name = pmid12052834>{{cite journal | vauthors = Yazgan O, Pfarr CM | title = Regulation of two JunD isoforms by Jun N-terminal kinases | journal = The Journal of Biological Chemistry | volume = 277 | issue = 33 | pages = 29710–8 | date = August 2002 | pmid = 12052834 | doi = 10.1074/jbc.M204552200 }}</ref><ref name = pmid11479302>{{cite journal | vauthors = Tada K, Okazaki T, Sakon S, Kobarai T, Kurosawa K, Yamaoka S, Hashimoto H, Mak TW, Yagita H, Okumura K, Yeh WC, Nakano H | title = Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death | journal = The Journal of Biological Chemistry | volume = 276 | issue = 39 | pages = 36530–4 | date = September 2001 | pmid = 11479302 | doi = 10.1074/jbc.M104837200 }}</ref><ref name = pmid8621542>{{cite journal | vauthors = Meyer CF, Wang X, Chang C, Templeton D, Tan TH | title = Interaction between c-Rel and the mitogen-activated protein kinase kinase kinase 1 signaling cascade in mediating kappaB enhancer activation | journal = The Journal of Biological Chemistry | volume = 271 | issue = 15 | pages = 8971–6 | date = April 1996 | pmid = 8621542 | doi = 10.1074/jbc.271.15.8971 }}</ref><ref name = pmid8586671>{{cite journal | vauthors = Cano E, Hazzalin CA, Kardalinou E, Buckle RS, Mahadevan LC | title = Neither ERK nor JNK/SAPK MAP kinase subtypes are essential for histone H3/HMG-14 phosphorylation or c-fos and c-jun induction | journal = Journal of Cell Science | volume = 108 ( Pt 11) | issue = 11 | pages = 3599–609 | date = November 1995 | pmid = 8586671 | doi = }}</ref><ref name = pmid9207092>{{cite journal | vauthors = Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T, Davis RJ | title = Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 14 | pages = 7337–42 | date = July 1997 | pmid = 9207092 | pmc = 23822 | doi = 10.1073/pnas.94.14.7337 | bibcode = 1997PNAS...94.7337T }}</ref>  
* [[Mothers against decapentaplegic homolog 3|SMAD3]]<ref name = pmid9732876>{{cite journal |vauthors=Zhang Y, Feng XH, Derynck R | title = Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription | volume = 394 | issue = 6696 | pages = 909–13 | year = 1998 | pmid = 9732876 | doi = 10.1038/29814 | journal = Nature |bibcode = 1998Natur.394..909Z }}</ref><ref name = pmid10903323>{{cite journal |vauthors=Verrecchia F, Pessah M, Atfi A, Mauviel A | title = Tumor necrosis factor-alpha inhibits transforming growth factor-beta /Smad signaling in human dermal fibroblasts via AP-1 activation | volume = 275 | issue = 39 | pages = 30226–31 | year = 2000 | pmid = 10903323 | doi = 10.1074/jbc.M005310200 | journal = Journal of Biological Chemistry }}</ref><ref name = pmid10220381>{{cite journal |vauthors=Liberati NT, Datto MB, Frederick JP, Shen X, Wong C, Rougier-Chapman EM, Wang XF | title = Smads bind directly to the Jun family of AP-1 transcription factors | volume = 96 | issue = 9 | pages = 4844–9 | year = 1999 | pmid = 10220381 | pmc = 21779 | doi =10.1073/pnas.96.9.4844 | bibcode = 1999PNAS...96.4844L | journal = Proceedings of the National Academy of Sciences of the United States of America }}</ref>  
* [[Mothers against decapentaplegic homolog 3|SMAD3]]<ref name = pmid9732876>{{cite journal | vauthors = Zhang Y, Feng XH, Derynck R | title = Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription | journal = Nature | volume = 394 | issue = 6696 | pages = 909–13 | date = August 1998 | pmid = 9732876 | doi = 10.1038/29814 | bibcode = 1998Natur.394..909Z }}</ref><ref name = pmid10903323>{{cite journal | vauthors = Verrecchia F, Pessah M, Atfi A, Mauviel A | title = Tumor necrosis factor-alpha inhibits transforming growth factor-beta /Smad signaling in human dermal fibroblasts via AP-1 activation | journal = The Journal of Biological Chemistry | volume = 275 | issue = 39 | pages = 30226–31 | date = September 2000 | pmid = 10903323 | doi = 10.1074/jbc.M005310200 }}</ref><ref name = pmid10220381>{{cite journal | vauthors = Liberati NT, Datto MB, Frederick JP, Shen X, Wong C, Rougier-Chapman EM, Wang XF | title = Smads bind directly to the Jun family of AP-1 transcription factors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 9 | pages = 4844–9 | date = April 1999 | pmid = 10220381 | pmc = 21779 | doi = 10.1073/pnas.96.9.4844 | bibcode = 1999PNAS...96.4844L }}</ref>  
* [[MyoD]]<ref name = pmid1310896>{{cite journal |vauthors=Bengal E, Ransone L, Scharfmann R, Dwarki VJ, Tapscott SJ, Weintraub H, Verma IM | title = Functional antagonism between c-Jun and MyoD proteins: a direct physical association | volume = 68 | issue = 3 | pages = 507–19 | year = 1992 | pmid = 1310896 | doi = 10.1016/0092-8674(92)90187-H| journal = Cell }}</ref>  
* [[MyoD]]<ref name = pmid1310896>{{cite journal | vauthors = Bengal E, Ransone L, Scharfmann R, Dwarki VJ, Tapscott SJ, Weintraub H, Verma IM | title = Functional antagonism between c-Jun and MyoD proteins: a direct physical association | journal = Cell | volume = 68 | issue = 3 | pages = 507–19 | date = February 1992 | pmid = 1310896 | doi = 10.1016/0092-8674(92)90187-H }}</ref>  
* [[NACA (gene)|NACA]]<ref name = pmid9488446>{{cite journal |vauthors=Moreau A, Yotov WV, Glorieux FH, St-Arnaud R | title = Bone-specific expression of the alpha chain of the nascent polypeptide-associated complex, a coactivator potentiating c-Jun-mediated transcription | volume = 18 | issue = 3 | pages = 1312–21 | year = 1998 | pmid = 9488446 | pmc = 108844 | doi = | journal = Molecular and Cellular Biology }}</ref>  
* [[NACA (gene)|NACA]]<ref name = pmid9488446>{{cite journal | vauthors = Moreau A, Yotov WV, Glorieux FH, St-Arnaud R | title = Bone-specific expression of the alpha chain of the nascent polypeptide-associated complex, a coactivator potentiating c-Jun-mediated transcription | journal = Molecular and Cellular Biology | volume = 18 | issue = 3 | pages = 1312–21 | date = March 1998 | pmid = 9488446 | pmc = 108844 | doi = }}</ref>  
* [[NFE2L1]]<ref name = pmid9872330/>  
* [[NFE2L1]]<ref name = pmid9872330/>  
* [[NFE2L2]]<ref name = pmid9872330/>  
* [[NFE2L2]]<ref name = pmid9872330/>  
* [[Nuclear receptor co-repressor 2|NCOR2]]<ref name = pmid10777532>{{cite journal |vauthors=Lee SK, Kim JH, Lee YC, Cheong J, Lee JW | title = Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-kappaB, and serum response factor | volume = 275 | issue = 17 | pages = 12470–4 | year = 2000 | pmid = 10777532 | doi = 10.1074/jbc.275.17.12470| journal = The Journal of Biological Chemistry }}</ref>  
* [[Nuclear receptor co-repressor 2|NCOR2]]<ref name = pmid10777532>{{cite journal | vauthors = Lee SK, Kim JH, Lee YC, Cheong J, Lee JW | title = Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-kappaB, and serum response factor | journal = The Journal of Biological Chemistry | volume = 275 | issue = 17 | pages = 12470–4 | date = April 2000 | pmid = 10777532 | doi = 10.1074/jbc.275.17.12470 }}</ref>  
* [[Nuclear receptor coactivator 1|NCOA1]]<ref name = pmid10567404>{{cite journal |vauthors=Lee SK, Anzick SL, Choi JE, Bubendorf L, Guan XY, Jung YK, Kallioniemi OP, Kononen J, Trent JM, Azorsa D, Jhun BH, Cheong JH, Lee YC, Meltzer PS, Lee JW | title = A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo | volume = 274 | issue = 48 | pages = 34283–93 | year = 1999 | pmid = 10567404 | doi = 10.1074/jbc.274.48.34283| journal = The Journal of Biological Chemistry }}</ref><ref name = pmid10847592>{{cite journal |vauthors=Lee SK, Na SY, Jung SY, Choi JE, Jhun BH, Cheong J, Meltzer PS, Lee YC, Lee JW | title = Activating protein-1, nuclear factor-kappaB, and serum response factor as novel target molecules of the cancer-amplified transcription coactivator ASC-2 | volume = 14 | issue = 6 | pages = 915–25 | year = 2000 | pmid = 10847592 | doi = 10.1210/mend.14.6.0471| journal = Molecular endocrinology (Baltimore, Md.) }}</ref><ref name = pmid9642216>{{cite journal |vauthors=Lee SK, Kim HJ, Na SY, Kim TS, Choi HS, Im SY, Lee JW | title = Steroid receptor coactivator-1 coactivates activating protein-1-mediated transactivations through interaction with the c-Jun and c-Fos subunits | volume = 273 | issue = 27 | pages = 16651–4 | year = 1998 | pmid = 9642216 | doi = 10.1074/jbc.273.27.16651| journal = The Journal of Biological Chemistry }}</ref>  
* [[Nuclear receptor coactivator 1|NCOA1]]<ref name = pmid10567404>{{cite journal | vauthors = Lee SK, Anzick SL, Choi JE, Bubendorf L, Guan XY, Jung YK, Kallioniemi OP, Kononen J, Trent JM, Azorsa D, Jhun BH, Cheong JH, Lee YC, Meltzer PS, Lee JW | title = A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo | journal = The Journal of Biological Chemistry | volume = 274 | issue = 48 | pages = 34283–93 | date = November 1999 | pmid = 10567404 | doi = 10.1074/jbc.274.48.34283 }}</ref><ref name = pmid10847592>{{cite journal | vauthors = Lee SK, Na SY, Jung SY, Choi JE, Jhun BH, Cheong J, Meltzer PS, Lee YC, Lee JW | title = Activating protein-1, nuclear factor-kappaB, and serum response factor as novel target molecules of the cancer-amplified transcription coactivator ASC-2 | journal = Molecular Endocrinology | volume = 14 | issue = 6 | pages = 915–25 | date = June 2000 | pmid = 10847592 | doi = 10.1210/mend.14.6.0471 }}</ref><ref name = pmid9642216>{{cite journal | vauthors = Lee SK, Kim HJ, Na SY, Kim TS, Choi HS, Im SY, Lee JW | title = Steroid receptor coactivator-1 coactivates activating protein-1-mediated transactivations through interaction with the c-Jun and c-Fos subunits | journal = The Journal of Biological Chemistry | volume = 273 | issue = 27 | pages = 16651–4 | date = July 1998 | pmid = 9642216 | doi = 10.1074/jbc.273.27.16651 }}</ref>  
* [[PIN1]]<ref name = pmid11432833>{{cite journal |vauthors=Wulf GM, Ryo A, Wulf GG, Lee SW, Niu T, Petkova V, Lu KP | title = Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1 | volume = 20 | issue = 13 | pages = 3459–72 | year = 2001 | pmid = 11432833 | pmc = 125530 | doi = 10.1093/emboj/20.13.3459 | journal = The EMBO Journal }}</ref>  
* [[PIN1]]<ref name = pmid11432833>{{cite journal | vauthors = Wulf GM, Ryo A, Wulf GG, Lee SW, Niu T, Petkova V, Lu KP | title = Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1 | journal = The EMBO Journal | volume = 20 | issue = 13 | pages = 3459–72 | date = July 2001 | pmid = 11432833 | pmc = 125530 | doi = 10.1093/emboj/20.13.3459 }}</ref>  
* [[RBM39]]<ref name = pmid11704680>{{cite journal |vauthors=Jung DJ, Na SY, Na DS, Lee JW | title = Molecular cloning and characterization of CAPER, a novel coactivator of activating protein-1 and estrogen receptors | volume = 277 | issue = 2 | pages = 1229–34 | year = 2002 | pmid = 11704680 | doi = 10.1074/jbc.M110417200 | journal = Journal of Biological Chemistry }}</ref>  
* [[RBM39]]<ref name = pmid11704680>{{cite journal | vauthors = Jung DJ, Na SY, Na DS, Lee JW | title = Molecular cloning and characterization of CAPER, a novel coactivator of activating protein-1 and estrogen receptors | journal = The Journal of Biological Chemistry | volume = 277 | issue = 2 | pages = 1229–34 | date = January 2002 | pmid = 11704680 | doi = 10.1074/jbc.M110417200 }}</ref>  
* [[RELA]]<ref name = pmid10488148/>  
* [[RELA]]<ref name = pmid10488148/>  
* [[Retinoblastoma protein|RB1]]<ref name = pmid10026157>{{cite journal |vauthors=Nishitani J, Nishinaka T, Cheng CH, Rong W, Yokoyama KK, Chiu R | title = Recruitment of the retinoblastoma protein to c-Jun enhances transcription activity mediated through the AP-1 binding site | volume = 274 | issue = 9 | pages = 5454–61 | year = 1999 | pmid = 10026157 | doi = 10.1074/jbc.274.9.5454| journal = The Journal of Biological Chemistry }}</ref>  
* [[Retinoblastoma protein|RB1]]<ref name = pmid10026157>{{cite journal | vauthors = Nishitani J, Nishinaka T, Cheng CH, Rong W, Yokoyama KK, Chiu R | title = Recruitment of the retinoblastoma protein to c-Jun enhances transcription activity mediated through the AP-1 binding site | journal = The Journal of Biological Chemistry | volume = 274 | issue = 9 | pages = 5454–61 | date = February 1999 | pmid = 10026157 | doi = 10.1074/jbc.274.9.5454 }}</ref>  
* [[RFWD2]]<ref name = pmid14739464>{{cite journal |vauthors=Wertz IE, O'Rourke KM, Zhang Z, Dornan D, Arnott D, Deshaies RJ, Dixit VM | title = Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase | volume = 303 | issue = 5662 | pages = 1371–4 | year = 2004 | pmid = 14739464 | doi = 10.1126/science.1093549 | journal = Science |bibcode = 2004Sci...303.1371W }}</ref><ref name = pmid12615916>{{cite journal |vauthors=Bianchi E, Denti S, Catena R, Rossetti G, Polo S, Gasparian S, Putignano S, Rogge L, Pardi R | title = Characterization of human constitutive photomorphogenesis protein 1, a RING finger ubiquitin ligase that interacts with Jun transcription factors and modulates their transcriptional activity | volume = 278 | issue = 22 | pages = 19682–90 | year = 2003 | pmid = 12615916 | doi = 10.1074/jbc.M212681200 | journal = Journal of Biological Chemistry }}</ref>  
* [[RFWD2]]<ref name = pmid14739464>{{cite journal | vauthors = Wertz IE, O'Rourke KM, Zhang Z, Dornan D, Arnott D, Deshaies RJ, Dixit VM | title = Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase | journal = Science | volume = 303 | issue = 5662 | pages = 1371–4 | date = February 2004 | pmid = 14739464 | doi = 10.1126/science.1093549 | bibcode = 2004Sci...303.1371W }}</ref><ref name = pmid12615916>{{cite journal | vauthors = Bianchi E, Denti S, Catena R, Rossetti G, Polo S, Gasparian S, Putignano S, Rogge L, Pardi R | title = Characterization of human constitutive photomorphogenesis protein 1, a RING finger ubiquitin ligase that interacts with Jun transcription factors and modulates their transcriptional activity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 22 | pages = 19682–90 | date = May 2003 | pmid = 12615916 | doi = 10.1074/jbc.M212681200 }}</ref>  
* [[RUNX1]]<ref name = pmid11274169/><ref name = pmid11641401/>
* [[RUNX1]]<ref name = pmid11274169/><ref name = pmid11641401/>
* [[RUNX2]]<ref name = pmid11274169>{{cite journal |vauthors=Hess J, Porte D, Munz C, Angel P | title = AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element | volume = 276 | issue = 23 | pages = 20029–38 | year = 2001 | pmid = 11274169 | doi = 10.1074/jbc.M010601200 | journal = Journal of Biological Chemistry }}</ref><ref name = pmid11641401>{{cite journal |vauthors=D'Alonzo RC, Selvamurugan N, Karsenty G, Partridge NC | title = Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation | volume = 277 | issue = 1 | pages = 816–22 | year = 2002 | pmid = 11641401 | doi = 10.1074/jbc.M107082200 | journal = Journal of Biological Chemistry }}</ref>  
* [[RUNX2]]<ref name = pmid11274169>{{cite journal | vauthors = Hess J, Porte D, Munz C, Angel P | title = AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element | journal = The Journal of Biological Chemistry | volume = 276 | issue = 23 | pages = 20029–38 | date = June 2001 | pmid = 11274169 | doi = 10.1074/jbc.M010601200 }}</ref><ref name = pmid11641401>{{cite journal | vauthors = D'Alonzo RC, Selvamurugan N, Karsenty G, Partridge NC | title = Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 1 | pages = 816–22 | date = January 2002 | pmid = 11641401 | doi = 10.1074/jbc.M107082200 }}</ref>  
* [[STAT1]]<ref name = pmid10490649>{{cite journal |vauthors=Zhang X, Wrzeszczynska MH, Horvath CM, Darnell JE | title = Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation | volume = 19 | issue = 10 | pages = 7138–46 | year = 1999 | pmid = 10490649 | pmc = 84707 | doi = | journal = Molecular and Cellular Biology }}</ref>  
* [[STAT1]]<ref name = pmid10490649>{{cite journal | vauthors = Zhang X, Wrzeszczynska MH, Horvath CM, Darnell JE | title = Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation | journal = Molecular and Cellular Biology | volume = 19 | issue = 10 | pages = 7138–46 | date = October 1999 | pmid = 10490649 | pmc = 84707 | doi = }}</ref>  
* [[STAT3]]<ref name = pmid10490649/>  
* [[STAT3]]<ref name = pmid10490649/>  
* [[TATA-binding protein|TBP]]<ref name = pmid7848298>{{cite journal |vauthors=Franklin CC, McCulloch AV, Kraft AS | title = In vitro association between the Jun protein family and the general transcription factors, TBP and TFIIB | volume = 305 | issue = Pt 3| pages = 967–74 | year = 1995 | pmid = 7848298 | pmc = 1136352 | doi = 10.1042/bj3050967| journal = The Biochemical Journal }}</ref> and
* [[TATA-binding protein|TBP]]<ref name = pmid7848298>{{cite journal | vauthors = Franklin CC, McCulloch AV, Kraft AS | title = In vitro association between the Jun protein family and the general transcription factors, TBP and TFIIB | journal = The Biochemical Journal | volume = 305 ( Pt 3) | issue = Pt 3 | pages = 967–74 | date = February 1995 | pmid = 7848298 | pmc = 1136352 | doi = 10.1042/bj3050967 }}</ref> and
* [[Transcription Factor II B|GTF2B]].<ref name = pmid7848298/>
* [[Transcription Factor II B|GTF2B]].<ref name = pmid7848298/>
{{Div col end}}
{{Div col end}}
Line 123: Line 126:
== Further reading ==
== Further reading ==
{{refbegin|35em}}
{{refbegin|35em}}
*{{cite journal |vauthors=Bohmann D, Bos TJ, Admon A, Nishimura T, Vogt PK, Tjian R | title = Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1 | journal = Science | volume = 238 | issue = 4832 | pages = 1386–92 |date=December 1987 | pmid = 2825349 | doi = 10.1126/science.2825349 |bibcode = 1987Sci...238.1386B }}
* {{cite journal | vauthors = Bohmann D, Bos TJ, Admon A, Nishimura T, Vogt PK, Tjian R | title = Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1 | journal = Science | volume = 238 | issue = 4832 | pages = 1386–92 | date = December 1987 | pmid = 2825349 | doi = 10.1126/science.2825349 | bibcode = 1987Sci...238.1386B }}
*{{cite journal | author=Rahmsdorf HJ |title=Jun: transcription factor and oncoprotein |journal=J. Mol. Med. |volume=74 |issue= 12 |pages= 725–47 |year= 1997 |pmid= 8974016 |doi=10.1007/s001090050077 }}
* {{cite journal | vauthors = Rahmsdorf HJ | title = Jun: transcription factor and oncoprotein | journal = Journal of Molecular Medicine | volume = 74 | issue = 12 | pages = 725–47 | date = December 1996 | pmid = 8974016 | doi = 10.1007/s001090050077 }}
*{{cite journal |vauthors=Liu JL, Kung HJ |title=Marek's disease herpesvirus transforming protein MEQ: a c-Jun analogue with an alternative life style |journal=Virus Genes |volume=21 |issue= 1–2 |pages= 51–64 |year= 2001 |pmid= 11022789 |doi=10.1023/A:1008132313289 }}
* {{cite journal | vauthors = Liu JL, Kung HJ | title = Marek's disease herpesvirus transforming protein MEQ: a c-Jun analogue with an alternative life style | journal = Virus Genes | volume = 21 | issue = 1-2 | pages = 51–64 | year = 2001 | pmid = 11022789 | doi = 10.1023/A:1008132313289 }}
*{{cite journal |vauthors=Velazquez Torres A, Gariglio Vidal P |title=[Possible role of transcription factor AP1 in the tissue-specific regulation of human papillomavirus] |journal=Rev. Invest. Clin. |volume=54 |issue= 3 |pages= 231–42 |year= 2002 |pmid= 12183893 |doi=  }}
* {{cite journal | vauthors = Velazquez Torres A, Gariglio Vidal P | title = [Possible role of transcription factor AP1 in the tissue-specific regulation of human papillomavirus] | journal = Revista De Investigacion Clinica; Organo Del Hospital De Enfermedades De La Nutricion | volume = 54 | issue = 3 | pages = 231–42 | year = 2002 | pmid = 12183893 | doi =  }}
*{{cite journal |vauthors=Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG |title=The activator protein-1 transcription factor in respiratory epithelium carcinogenesis |journal=Mol. Cancer Res. |volume=5 |issue= 2 |pages= 109–20 |year= 2007 |pmid= 17314269 |doi= 10.1158/1541-7786.MCR-06-0311 }}
* {{cite journal | vauthors = Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG | title = The activator protein-1 transcription factor in respiratory epithelium carcinogenesis | journal = Molecular Cancer Research | volume = 5 | issue = 2 | pages = 109–20 | date = February 2007 | pmid = 17314269 | doi = 10.1158/1541-7786.MCR-06-0311 }}
{{refend}}
{{refend}}


Latest revision as of 12:27, 22 October 2018

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c-Jun is a protein that in humans is encoded by the JUN gene. c-Jun, in combination with c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the JNK pathway but has also a phosphorylation-independent function. c-jun knockout is lethal, but transgenic animals with a mutated c-jun that cannot be phosphorylated (termed c-junAA) can survive.

This gene is the putative transforming gene of avian sarcoma virus 17. It encodes a protein that is highly similar to the viral protein, and that interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.[1]

Function

Regulation

Both Jun and its dimerization partners in AP-1 formation are subject to regulation by diverse extracellular stimuli, which include peptide growth factors, pro-inflammatory cytokines, oxidative and other forms of cellular stress, and UV irradiation. For example, UV irradiation is a potent inducer for elevated c-jun expression.[2]

The c-jun transcription is autoregulated by its own product, Jun. The binding of Jun (AP-1) to a high-affinity AP-1 binding site in the jun promoter region induces jun transcription. This positive autoregulation by stimulating its own transcription may be a mechanism for prolonging the signals from extracellular stimuli. This mechanism can have biological significance for the activity of c-jun in cancer.[3]

Also, the c-jun activities can be regulated by the ERK pathway. Constitutively active ERK is found to increase c-jun transcription and stability through CREB and GSK3. This results in activated c-jun and its downstream targets such as RACK1 and cyclin D1. RACK1 can enhance JNK activity, and activated JNK signaling subsequently exerts regulation on c-jun activity.[4]

Phosphorylation of Jun at serines 63 and 73 and threonine 91 and 93 increases transcription of the c-jun target genes.[5] Therefore, regulation of c-jun activity can be achieved through N-terminal phosphorylation by the Jun N-terminal kinases (JNKs). It is shown that Jun’s activity (AP-1 activity) in stress-induced apoptosis and cellular proliferation is regulated by its N-terminal phosphorylation.[6] Another study showed that oncogenic transformation by ras and fos also requires Jun N-terminal phosphorylation at Serine 63 and 73.[7]

Cell cycle progression

Studies have shown that c-jun is required for progression through the G1 phase of the cell cycle, and c-jun null cells show increased G1 arrest. C-jun regulates the transcriptional level of cyclin D1, which is a major Rb kinase. Rb is a growth suppressor, and it is inactivated by phosphorylation. Therefore, c-jun is required for maintaining sufficient cyclin D1 kinase activity and allowing cell cycle progression.[2]

In cells absent of c-jun, the expression of p53 (cell cycle arrest inducer) and p21 (CDK inhibitor and p53 target gene) is increased, and those cells exhibit cell cycle defect. Overexpression of c-jun in cells results in decreased level of p53 and p21, and exhibits accelerated cell proliferation. C-jun represses p53 transcription by binding to a variant AP-1 site in the p53 promoter. Those results indicate that c-jun downregulates p53 to control cell cycle progression.[8]

Anti-apoptotic activity

UV irradiation can activate c-jun expression and the JNK signaling pathway. C-jun protects cells from UV-induced apoptosis, and it cooperates with NF-κB to prevent apoptosis induced by TNFα. The protection from apoptosis by c-jun requires serines 63/73 (involved in phosphorylation of Jun), which is not required in c-jun-mediated G1 progress. This suggests that c-jun regulates cell cycle progression and apoptosis through two separated mechanisms.[2]

A study utilized liver-specific inactivation of c-jun in hepatocellular carcinoma, which showed impaired tumor development correlated with increased level of p53 protein and the mRNA level of the p53 target gene noxa. Also, c-jun can protect hepatocytes from apoptosis, as hepatocytes lacking c-jun showed increased sensitivity to TNFα-induced apoptosis. In those hepatocytes lacking c-jun, deletion of p53 can restore resistance toward TNFα. Those results indicate that c-jun antagonizes the proapoptotic activity of p53 in liver tumor.[9]

Clinical significance

It is known that c-jun plays a role in cellular proliferation and apoptosis of the endometrium throughout the menstrual cycle. The cyclic change of the c-jun protein levels is significant in the proliferation and apoptosis of glandular epithelial cells. The persistent stromal expression of c-jun protein may prevent stromal cells from entering into apoptosis during the late secretory phase.[10]

Cancer

C-jun is a proto-oncogene (its protein is Jun) and is the cellular homolog of the viral oncoprotein v-jun.[2] Jun is the first discovered oncogenic transcription factor.[11]

In a study using non-small cell lung cancers (NSCLC), c-jun was found to be overexpressed in 31% of the cases in primary and metastatic lung tumors, whereas normal conducting airway and alveolar epithelia in general did not express c-jun.[12]

A study with a group consisted of 103 cases of phase I/II invasive breast cancers showed that activated c-jun is expressed predominantly at the invasive front of breast cancer and is associated with proliferation and angiogenesis.[13]

Tumor initiation

A study was done with liver-specific inactivation of c-jun at different stages of tumor development in mice with chemically induced hepatocellular carcinomas. The result indicates that c-jun is required at the early stage of tumor development, and deletion of c-jun can largely suppress tumor formation. Also, c-jun is required for tumor cell survival between the initiation and progression stages. In contrast to that, inactivation of c-jun in advanced tumors does not impair tumor progression.[9]

Breast cancer

Overexpression of c-jun in MCF-7 cells can result in overall increased aggressiveness, as shown by increased cellular motility, increased expression of a matrix-degrading enzyme MMP-9, increased in vitro chemoinvasion, and tumor formation in nude mice in the absence of exogenous estrogens. The MCF-7 cells with c-jun overexpression became unresponsive to estrogen and tamoxifen, thus c-jun overexpression is proposed to lead to an estrogen-independent phenotype in breast cancer cells. The observed phenotype for MCF-7 cells with c-jun overexpression is similar to that observed clinically in advanced breast cancer, which had become hormone unresponsive.[14]

The invasive phenotype contributed by c-jun overexpression is confirmed in another study. In addition, this study showed increased in vivo liver metastasis by the breast cancer with c-jun overexpression. This finding suggests that c-jun plays a critical role in the metastasis of breast cancer.[15]

In mammary tumors, endogenous c-jun was found to play a key role in ErbB2-induced migration and invasion of mammary epithelial cells. Jun transcriptionally activates the promoters of SCF (stem cell factor) and CCL5. The induced SCF and CCL5 expression promotes a self-renewing mammary epithelial population. It suggests that c-jun mediates the expansion of breast cancer stem cells to enhance tumor invasiveness.[16]

Cellular differentiation

Ten undifferentiated and highly aggressive sarcomas showed amplification of the jun gene and JUN overexpression at both RNA and protein levels. Overexpression of c-jun in 3T3-L1 cells (a preadipocytic non-tumoral cell line that resembles human liposarcoma) can block or delay adipocytic differentiation of those cells.[17]

Nerve and Spinal Cord Regeneration

Peripheral nerve injury in rodents rapidly activates JNK signaling which in turn activates c-Jun. In contrast, nerve injury in the central nervous system does not. c-Jun is sufficient to promote axon regeneration in both the peripheral and central nervous systems as overexpression in both dorsal root ganglion neurons and cortical neurons leads to increased regeneration. [18]

As anti-cancer drug target

A study showed that oncogenic transformation by ras and fos requires Jun N-terminal phosphorylation at Serine 63 and 73 by the Jun N- terminal kinases (JNK). In this study, the induced skin tumor and osteosarcoma showed impaired development in mice with a mutant Jun incapable of N-terminal phosphorylation.[7] Also, in a mouse model of intestinal cancer, genetic abrogation of Jun N-terminal phosphorylation or gut-specific c-jun inactivation attenuated cancer development and prolonged lifespan.[5] Therefore, targeting the N-terminal phosphorylation of Jun (or the JNK signaling pathway) can be a potential strategy for inhibiting tumor growth.

In melanoma-derived B16-F10 cancer cells, c-jun inactivation by a pharmacological JNK/jun inhibitor SP combined with JunB knockdown can result in cytotoxic effect, leading to cell arrest and apoptosis. This anti-JunB /Jun strategy can increase the survival of mice inoculated with tumor cells, which suggests a potential antitumor strategy through Jun and JunB inhibition.[19]

Anti-cancer property of c-jun

Most research results show that c-jun contributes to tumor initiation and increased invasiveness. However, a few studies discovered some alternative activities of c-jun, suggesting that c-jun may actually be a double-edge sword in cancer.

p16INK4a

p16INK4a is a tumor suppressor and a cell cycle inhibitor, and a study shows that c-jun acts as “bodyguard” to p16INK4a by preventing methylation of the p16INK4a promoter. Therefore, c-jun can prevent silencing of the gene p16INK4a.[20]

Tylophorine

Tylophorine is a type of plant-derived alkaloid with anticancer activity by inducing cell cycle arrest. A study demonstrated that tylophorine treatment increased c-jun protein accumulation. Then c-jun expression in conjunction with tylophorine promotes G1 arrest in carcinoma cells through the downregulation of cyclin A2. Therefore, the result indicates that the anticancer mechanism of tylophorine is mediated through c-jun.[21]

Interactions

C-jun has been shown to interact with:

See also

References

  1. ↑ "Entrez Gene: JUN jun oncogene".
  2. ↑ 2.0 2.1 2.2 2.3 Wisdom R, Johnson RS, Moore C (January 1999). "c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms". The EMBO Journal. 18 (1): 188–97. doi:10.1093/emboj/18.1.188. PMC 1171114. PMID 9878062.
  3. ↑ Angel P, Hattori K, Smeal T, Karin M (December 1988). "The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1". Cell. 55 (5): 875–85. doi:10.1016/0092-8674(88)90143-2. PMID 3142689.
  4. ↑ Lopez-Bergami P, Huang C, Goydos JS, Yip D, Bar-Eli M, Herlyn M, Smalley KS, Mahale A, Eroshkin A, Aaronson S, Ronai Z (May 2007). "Rewired ERK-JNK signaling pathways in melanoma". Cancer Cell. 11 (5): 447–60. doi:10.1016/j.ccr.2007.03.009. PMC 1978100. PMID 17482134.
  5. ↑ 5.0 5.1 Nateri AS, Spencer-Dene B, Behrens A (September 2005). "Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development". Nature. 437 (7056): 281–5. Bibcode:2005Natur.437..281N. doi:10.1038/nature03914. PMID 16007074.
  6. ↑ Behrens A, Sibilia M, Wagner EF (March 1999). "Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation". Nature Genetics. 21 (3): 326–9. doi:10.1038/6854. PMID 10080190.
  7. ↑ 7.0 7.1 Behrens A, Jochum W, Sibilia M, Wagner EF (May 2000). "Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation". Oncogene. 19 (22): 2657–63. doi:10.1038/sj.onc.1203603. PMID 10851065.
  8. ↑ Schreiber M, Kolbus A, Piu F, Szabowski A, Möhle-Steinlein U, Tian J, Karin M, Angel P, Wagner EF (March 1999). "Control of cell cycle progression by c-Jun is p53 dependent". Genes & Development. 13 (5): 607–19. doi:10.1101/gad.13.5.607. PMC 316508. PMID 10072388.
  9. ↑ 9.0 9.1 Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, Wagner EF (January 2003). "Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53". Cell. 112 (2): 181–92. doi:10.1016/S0092-8674(03)00042-4. PMID 12553907.
  10. ↑ Udou T, Hachisuga T, Tsujioka H, Kawarabayashi T (2004). "The role of c-jun protein in proliferation and apoptosis of the endometrium throughout the menstrual cycle". Gynecologic and Obstetric Investigation. 57 (3): 121–6. doi:10.1159/000075701. PMID 14691341.
  11. ↑ Vogt PK (June 2002). "Fortuitous convergences: the beginnings of JUN". Nature Reviews. Cancer. 2 (6): 465–9. doi:10.1038/nrc818. PMID 12189388.
  12. ↑ Szabo E, Riffe ME, Steinberg SM, Birrer MJ, Linnoila RI (January 1996). "Altered cJUN expression: an early event in human lung carcinogenesis". Cancer Research. 56 (2): 305–15. PMID 8542585.
  13. ↑ Vleugel MM, Greijer AE, Bos R, van der Wall E, van Diest PJ (June 2006). "c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer". Human Pathology. 37 (6): 668–74. doi:10.1016/j.humpath.2006.01.022. PMID 16733206.
  14. ↑ Smith LM, Wise SC, Hendricks DT, Sabichi AL, Bos T, Reddy P, Brown PH, Birrer MJ (October 1999). "cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype". Oncogene. 18 (44): 6063–70. doi:10.1038/sj.onc.1202989. PMID 10557095.
  15. ↑ Zhang Y, Pu X, Shi M, Chen L, Song Y, Qian L, Yuan G, Zhang H, Yu M, Hu M, Shen B, Guo N (August 2007). "Critical role of c-Jun overexpression in liver metastasis of human breast cancer xenograft model". BMC Cancer. 7: 145. doi:10.1186/1471-2407-7-145. PMC 1959235. PMID 17672916.
  16. ↑ Jiao X, Katiyar S, Willmarth NE, Liu M, Ma X, Flomenberg N, Lisanti MP, Pestell RG (March 2010). "c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion". The Journal of Biological Chemistry. 285 (11): 8218–26. doi:10.1074/jbc.M110.100792. PMC 2832973. PMID 20053993.
  17. ↑ Mariani O, Brennetot C, Coindre JM, Gruel N, Ganem C, Delattre O, Stern MH, Aurias A (April 2007). "JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas". Cancer Cell. 11 (4): 361–74. doi:10.1016/j.ccr.2007.02.007. PMID 17418412.
  18. ↑ Mahar M, Cavalli V (June 2018). "Intrinsic mechanisms of neuronal axon regeneration". Nature Reviews. Neuroscience. 19 (6): 323–337. doi:10.1038/s41583-018-0001-8. PMC 5987780. PMID 29666508.
  19. ↑ Gurzov EN, Bakiri L, Alfaro JM, Wagner EF, Izquierdo M (January 2008). "Targeting c-Jun and JunB proteins as potential anticancer cell therapy". Oncogene. 27 (5): 641–52. doi:10.1038/sj.onc.1210690. PMID 17667939.
  20. ↑ Kollmann K, Heller G, Sexl V (May 2011). "c-JUN prevents methylation of p16(INK4a) (and Cdk6): the villain turned bodyguard". Oncotarget. 2 (5): 422–7. doi:10.18632/oncotarget.279. PMC 3248190. PMID 21789792.
  21. ↑ Yang CW, Lee YZ, Hsu HY, Wu CM, Chang HY, Chao YS, Lee SJ (June 2013). "c-Jun-mediated anticancer mechanisms of tylophorine". Carcinogenesis. 34 (6): 1304–14. doi:10.1093/carcin/bgt039. PMID 23385061.
  22. ↑ Newell CL, Deisseroth AB, Lopez-Berestein G (July 1994). "Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene". Journal of Leukocyte Biology. 56 (1): 27–35. PMID 8027667.
  23. ↑ Kara CJ, Liou HC, Ivashkiv LB, Glimcher LH (April 1990). "A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain". Molecular and Cellular Biology. 10 (4): 1347–57. PMC 362236. PMID 2320002.
  24. ↑ 24.0 24.1 Hai T, Curran T (May 1991). "Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity". Proceedings of the National Academy of Sciences of the United States of America. 88 (9): 3720–4. Bibcode:1991PNAS...88.3720H. doi:10.1073/pnas.88.9.3720. PMC 51524. PMID 1827203.
  25. ↑ Sato N, Sadar MD, Bruchovsky N, Saatcioglu F, Rennie PS, Sato S, Lange PH, Gleave ME (July 1997). "Androgenic induction of prostate-specific antigen gene is repressed by protein-protein interaction between the androgen receptor and AP-1/c-Jun in the human prostate cancer cell line LNCaP". The Journal of Biological Chemistry. 272 (28): 17485–94. doi:10.1074/jbc.272.28.17485. PMID 9211894.
  26. ↑ Jung DJ, Sung HS, Goo YW, Lee HM, Park OK, Jung SY, Lim J, Kim HJ, Lee SK, Kim TS, Lee JW, Lee YC (July 2002). "Novel transcription coactivator complex containing activating signal cointegrator 1". Molecular and Cellular Biology. 22 (14): 5203–11. doi:10.1128/MCB.22.14.5203-5211.2002. PMC 139772. PMID 12077347.
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  28. ↑ Chen BP, Wolfgang CD, Hai T (March 1996). "Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10". Molecular and Cellular Biology. 16 (3): 1157–68. doi:10.1128/MCB.16.3.1157. PMC 231098. PMID 8622660.
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Further reading

  • Bohmann D, Bos TJ, Admon A, Nishimura T, Vogt PK, Tjian R (December 1987). "Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1". Science. 238 (4832): 1386–92. Bibcode:1987Sci...238.1386B. doi:10.1126/science.2825349. PMID 2825349.
  • Rahmsdorf HJ (December 1996). "Jun: transcription factor and oncoprotein". Journal of Molecular Medicine. 74 (12): 725–47. doi:10.1007/s001090050077. PMID 8974016.
  • Liu JL, Kung HJ (2001). "Marek's disease herpesvirus transforming protein MEQ: a c-Jun analogue with an alternative life style". Virus Genes. 21 (1–2): 51–64. doi:10.1023/A:1008132313289. PMID 11022789.
  • Velazquez Torres A, Gariglio Vidal P (2002). "[Possible role of transcription factor AP1 in the tissue-specific regulation of human papillomavirus]". Revista De Investigacion Clinica; Organo Del Hospital De Enfermedades De La Nutricion. 54 (3): 231–42. PMID 12183893.
  • Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG (February 2007). "The activator protein-1 transcription factor in respiratory epithelium carcinogenesis". Molecular Cancer Research. 5 (2): 109–20. doi:10.1158/1541-7786.MCR-06-0311. PMID 17314269.

External links

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