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{{Infobox_gene}}
{{Infobox_gene}}


'''Oct-4''' ([[Octamer transcription factor|octamer]]-binding [[transcription factor]] 4) also known as '''POU5F1''' (POU domain, class 5, transcription factor 1) is a [[protein]] that in humans is encoded by the ''POU5F1'' [[gene]].<ref name="pmid1408763">{{cite journal | vauthors = Takeda J, Seino S, Bell GI | title = Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues | journal = Nucleic Acids Research | volume = 20 | issue = 17 | pages = 4613–20 | date = Sep 1992 | pmid = 1408763 | pmc = 334192 | doi = 10.1093/nar/20.17.4613 }}</ref> Oct-4 is a [[homeobox|homeodomain transcription factor]] of the [[POU family]]. This protein is critically involved in the self-renewal of undifferentiated embryonic [[stem cell]]s.<ref>[http://jura.wi.mit.edu/young_public/hESregulation/index.html Young Lab- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells] at [[MIT]]</ref> As such, it is frequently used as a [[biomarker (cell)|marker]] for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.<ref name="pmid10742100">{{cite journal | vauthors = Niwa H, Miyazaki J, Smith AG | title = Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells | journal = Nature Genetics | volume = 24 | issue = 4 | pages = 372–6 | date = Apr 2000 | pmid = 10742100 | doi = 10.1038/74199 }}</ref>
'''Oct-4''' ([[oligomer|octamer]]-binding [[transcription factor]] 4), also known as '''POU5F1''' ([[POU domain]], class 5, transcription factor 1), is a [[protein]] that in humans is encoded by the ''POU5F1'' [[gene]].<ref name="pmid1408763">{{cite journal | vauthors = Takeda J, Seino S, Bell GI | title = Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues | journal = Nucleic Acids Research | volume = 20 | issue = 17 | pages = 4613–20 | date = Sep 1992 | pmid = 1408763 | pmc = 334192 | doi = 10.1093/nar/20.17.4613 }}</ref> Oct-4 is a [[homeobox|homeodomain transcription factor]] of the [[POU family]]. It is critically involved in the self-renewal of undifferentiated [[embryonic stem cell]]s.<ref>[http://jura.wi.mit.edu/young_public/hESregulation/index.html Young Lab- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells] {{webarchive|url=https://web.archive.org/web/20090628185523/http://jura.wi.mit.edu/young_public/hESregulation/index.html |date=2009-06-28 }} at [[MIT]]</ref> As such, it is frequently used as a [[biomarker (cell)|marker]] for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.<ref name="pmid10742100">{{cite journal | vauthors = Niwa H, Miyazaki J, Smith AG | title = Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells | journal = Nature Genetics | volume = 24 | issue = 4 | pages = 372–6 | date = Apr 2000 | pmid = 10742100 | doi = 10.1038/74199 }}</ref>


The [[Oligomer|octamer]] (made of eight units) in this family of transcription factors is the DNA [[nucleotide]] sequence "ATTTGCAT", the etymology for the naming of the [[octamer transcription factor]].<ref>{{cite journal | vauthors = Petryniak B, Staudt LM, Postema CE, McCormack WT, Thompson CB | title = Characterization of chicken octamer-binding proteins demonstrates that POU domain-containing homeobox transcription factors have been highly conserved during vertebrate evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 3 | pages = 1099–103 | date = Feb 1990 | pmid = 1967834 | pmc = 53418 | doi = 10.1073/pnas.87.3.1099 }}</ref>
Oct-4 is a member of the [[octamer transcription factor]] family, so named because they bind the octameric (8-unit) DNA [[nucleotide]] sequence "ATTTGCAT".<ref>{{cite journal | vauthors = Petryniak B, Staudt LM, Postema CE, McCormack WT, Thompson CB | title = Characterization of chicken octamer-binding proteins demonstrates that POU domain-containing homeobox transcription factors have been highly conserved during vertebrate evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 3 | pages = 1099–103 | date = Feb 1990 | pmid = 1967834 | pmc = 53418 | doi = 10.1073/pnas.87.3.1099 }}</ref>


==Expression and function==
==Expression and function==
Oct-4 transcription factor is initially active as a maternal factor in the oocyte but remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors.<ref>{{cite journal | vauthors = Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW | title = POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors | journal = Cancer Research | volume = 63 | issue = 9 | pages = 2244–50 | date = May 2003 | pmid = 12727846 }}</ref>  Gene knockdown of Oct-4 promotes [[cellular differentiation|differentiation]], thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.<ref>{{cite journal | vauthors = Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ | title = High-efficiency RNA interference in human embryonic stem cells | journal = Stem Cells | volume = 23 | issue = 3 | pages = 299–305 | date = Mar 2005 | pmid = 15749924 | doi = 10.1634/stemcells.2004-0252 }}</ref> Oct-4 can form a heterodimer with [[Sox2]], so that these two proteins bind DNA together.<ref name=Rodda2005>{{cite journal | vauthors = Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P | title = Transcriptional regulation of nanog by OCT4 and SOX2 | journal = The Journal of Biological Chemistry | volume = 280 | issue = 26 | pages = 24731–7 | date = Jul 2005 | pmid = 15860457 | doi = 10.1074/jbc.M502573200 | url = http://www.jbc.org/cgi/content/full/280/26/24731 }}</ref>
Oct-4 transcription factor is initially active as a [[maternal effect|maternal factor]] in the [[oocyte]] and remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors.<ref>{{cite journal | vauthors = Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW | title = POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors | journal = Cancer Research | volume = 63 | issue = 9 | pages = 2244–50 | date = May 2003 | pmid = 12727846 }}</ref>  Gene knockdown of Oct-4 promotes [[cellular differentiation|differentiation]], demonstrating a role for these factors in human embryonic stem cell self-renewal.<ref>{{cite journal | vauthors = Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ | title = High-efficiency RNA interference in human embryonic stem cells | journal = Stem Cells | volume = 23 | issue = 3 | pages = 299–305 | date = Mar 2005 | pmid = 15749924 | doi = 10.1634/stemcells.2004-0252 }}</ref> Oct-4 can form a heterodimer with [[Sox2]], so that these two proteins bind DNA together.<ref name=Rodda2005>{{cite journal | vauthors = Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P | title = Transcriptional regulation of nanog by OCT4 and SOX2 | journal = The Journal of Biological Chemistry | volume = 280 | issue = 26 | pages = 24731–7 | date = Jul 2005 | pmid = 15860457 | doi = 10.1074/jbc.M502573200 | url = http://www.jbc.org/cgi/content/full/280/26/24731 }}</ref>


Mouse embryos that are Oct-4-deficient or have low expression levels of Oct-4 fail to form the inner cell mass, lose pluripotency and differentiate into [[trophectoderm]]. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.
Mouse embryos that are Oct-4 deficient or have low expression levels of Oct-4 fail to form the [[inner cell mass]], lose [[pluripotency]], and differentiate into [[trophectoderm]]. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.


== Orthologs ==
== Orthologs ==
[[Homology (biology)#Orthology|Orthologs]] of Oct-4 exist in humans and several other species including:
[[Homology (biology)#Orthology|Orthologs]] of Oct-4 in humans and other species include:
{| class="wikitable"
{| class="wikitable"
| '''Species''' || '''Entrez GeneID'''  || '''Chromosome''' || '''Location''' || '''RefSeq (mRNA)''' || '''RefSeq (protein)'''
| '''Species''' || '''Entrez GeneID'''  || '''Chromosome''' || '''Location''' || '''RefSeq (mRNA)''' || '''RefSeq (protein)'''
  |-  
  |-  
  | [[Mus musculus]] || [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=18999 18999] || 17,17 B1; 17 19.23 cM || NC_000083.4, 35114104..35118822 (Plus Strand) || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_013633.1 NM_013633.1] || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_038661.1 NP_038661.1]  
  | ''[[Mus musculus]]'' (mouse) || [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=18999 18999] || 17,17 B1; 17 19.23 cM || NC_000083.4, 35114104..35118822 (Plus Strand) || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_013633.1 NM_013633.1] || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_038661.1 NP_038661.1]  
  |-  
  |-  
  | [[Homo sapiens]] || [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=5460 5460] || 6, 6p21.31  || NC_000006.10, 31246432-31240107 (Minus Strand) || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_002701.3 NM_002701.3]  || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_002692.2 NP_002692.2]  (full length isoform) <br /> [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_002692.1 NP_002692.1] (N-terminal truncated isoform)
  | ''[[Homo sapiens]]'' (human) || [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=5460 5460] || 6, 6p21.31  || NC_000006.10, 31246432-31240107 (Minus Strand) || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_002701.3 NM_002701.3]  || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_002692.2 NP_002692.2]  (full length isoform) <br /> [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_002692.1 NP_002692.1] (N-terminal truncated isoform)
  |-  
  |-  
  | [[Rattus norvegicus]] || [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=294562 294562] || 20 || NW_001084776, 650467-655015 (Minus strand)  || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_001009178.1 NM_001009178] || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_001009178.1 NP_001009178]  
  | ''[[Rattus norvegicus]]'' (rat) || [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=294562 294562] || 20 || NW_001084776, 650467-655015 (Minus strand)  || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_001009178.1 NM_001009178] || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_001009178.1 NP_001009178]  
  |-  
  |-  
  | [[Danio rerio]] (Zebrafish)|| [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=30333 303333] || 21 || NC_007127.1, 27995548-28000317 (Minus strand) ||  [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_131112.1 NM_131112] || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_571187.1 NP_571187]
  | ''[[Danio rerio]]'' (zebrafish) || [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=30333 303333] || 21 || NC_007127.1, 27995548-28000317 (Minus strand) ||  [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_131112.1 NM_131112] || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_571187.1 NP_571187]
|}
|}


== Structural Information ==
== Structure ==
Oct-4 contains the following [[protein domain]]s:
Oct-4 contains the following [[protein domain]]s:
{| class="wikitable"
{| class="wikitable"
Line 34: Line 34:
| [[POU domain]] || Found in Pit-Oct-Unc transcription factors || 75
| [[POU domain]] || Found in Pit-Oct-Unc transcription factors || 75
|-
|-
| [[Homeodomain fold|Homeodomain]] || DNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homo- and/or heterodimers, in a sequence-specific manner. || 59
| [[Homeodomain fold|Homeodomain]] || DNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homodimers and/or heterodimers in a sequence-specific manner. || 59
|}
|}


Line 43: Line 43:


=== Animal model ===
=== Animal model ===
In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem (ES) cells to determine requirements for Oct-4 in the maintenance of developmental potency.<ref name="pmid10742100"/> Although transcriptional determination has usually been considered as a binary on-off control system, they found that the precise level of Oct-4 governs 3 distinct fates of ES cells. A less-than-2-fold increase in expression causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down regulation induces divergent developmental programs. Changes to Oct-4 levels do not independently promote differentiation, but are also controlled by levels of [[SOX2]]. A decrease in Sox2 accompanies increased levels of Oct-4 to promote a mesendodermal fate, with Oct-4 actively inhibiting ectodermal differentiation. Repressed Oct-4 levels that lead to ectodermal differentiation are accompanied by an increase in Sox2, which effectively inhibits mesendodermal differentiation.<ref name = "Thomson_2011">{{cite journal | vauthors = Thomson M, Liu SJ, Zou LN, Smith Z, Meissner A, Ramanathan S | title = Pluripotency factors in embryonic stem cells regulate differentiation into germ layers | journal = Cell | volume = 145 | issue = 6 | pages = 875–89 | date = June 2011 | pmid = 21663792 | doi = 10.1016/j.cell.2011.05.017 }}</ref> Niwa et al. suggested that their findings established a role for Oct-4 as a [[master regulator]] of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyzes.
In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem cells to determine requirements for Oct-4 in the maintenance of developmental potency.<ref name="pmid10742100"/> Although transcriptional determination has often been considered as a binary on-off control system, they found that the precise level of Oct-4 governs 3 distinct fates of ES cells. An increase in expression of less than 2-fold causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down-regulation induces divergent developmental programs. Changes to Oct-4 levels do not independently promote differentiation, but are also controlled by levels of [[Sox2]]. A decrease in Sox2 accompanies increased levels of Oct-4 to promote a mesendodermal fate, with Oct-4 actively inhibiting ectodermal differentiation. Repressed Oct-4 levels that lead to ectodermal differentiation are accompanied by an increase in Sox2, which effectively inhibits mesendodermal differentiation.<ref name = "Thomson_2011">{{cite journal | vauthors = Thomson M, Liu SJ, Zou LN, Smith Z, Meissner A, Ramanathan S | title = Pluripotency factors in embryonic stem cells regulate differentiation into germ layers | journal = Cell | volume = 145 | issue = 6 | pages = 875–89 | date = June 2011 | pmid = 21663792 | doi = 10.1016/j.cell.2011.05.017 }}</ref> Niwa et al. suggested that their findings established a role for Oct-4 as a [[master regulator]] of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyzes.


The transcription factors Oct-4, Sox2 and Nanog are part of a complex regulatory network with Oct-4 and Sox2 capable of directly regulating Nanog by binding to its promoter, and are essential for maintaining the self-renewing undifferentiated state of the [[inner cell mass]] of the blastocyst, [[embryonic stem cell]] lines (which are cell lines derived from the inner cell mass), and induced pluripotent stem (iPS) cells.<ref name=Rodda2005/> While differential up and down-regulation of Oct-4 and Sox2 has been shown to promote differentiation, down-regualtion of Nanog must occur in order for differentiation of proceed.<ref name = "Thomson_2011"/>
The transcription factors Oct-4, Sox2 and Nanog are part of a complex regulatory network with Oct-4 and Sox2 capable of directly regulating Nanog by binding to its promoter, and are essential for maintaining the self-renewing undifferentiated state of the inner cell mass of the blastocyst, [[embryonic stem cell]] lines (which are cell lines derived from the inner cell mass), and induced pluripotent stem cells.<ref name=Rodda2005/> While differential up- and down-regulation of Oct-4 and Sox2 has been shown to promote differentiation, down-regulation of Nanog must occur for differentiation to proceed.<ref name = "Thomson_2011"/>


==Role in Reprogramming==
==Role in reprogramming==


Oct-4 is one of the transcription factors used to create [[induced pluripotent stem cell]]s, together with [[Sox2]],  [[Kruppel-like factors|Klf4]] and often c-[[Myc]] in mouse,<ref>{{cite journal | vauthors = Okita K, Ichisaka T, Yamanaka S | title = Generation of germline-competent induced pluripotent stem cells | journal = Nature | volume = 448 | issue = 7151 | pages = 313–7 | date = Jul 2007 | pmid = 17554338 | doi = 10.1038/nature05934 }}</ref><ref>{{cite journal | vauthors = Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R | title = In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state | journal = Nature | volume = 448 | issue = 7151 | pages = 318–24 | date = Jul 2007 | pmid = 17554336 | doi = 10.1038/nature05944 }}</ref><ref>{{cite journal | vauthors = Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K | title = Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution | journal = Cell Stem Cell | volume = 1 | issue = 1 | pages = 55–70 | date = Jun 2007 | pmid = 18371336 | doi = 10.1016/j.stem.2007.05.014 }}</ref> demonstrating its capacity to induce an embryonic stem cell-like state. This effect has also been seen with the [[Thomson reprogramming factors]], reverting human fibroblast cells to iPSCs through Oct-4, along with Sox2, Nanog, and Lin28.<ref>{{cite journal  |vauthors=Yu J, Vodyanik MA, etal | title = Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells | journal = [[Science (journal)|Science]] | doi = 10.1126/science.1151526 | pmid = 18029452 | year = 2007 | volume = 318 | issue = 5858 | pages = 1917–1920}}</ref>  It was later deterimined that only two of these four factors, Oct4 and Klf4 were sufficient to reprogram mouse adult neural stem cells.<ref name="pmid18594515">{{cite journal | vauthors = Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR | title = Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors | journal = Nature | volume = 454 | issue = 7204 | pages = 646–50 | date = Jul 2008 | pmid = 18594515 | doi = 10.1038/nature07061 }}</ref>  Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.<ref name="Kim_2009">{{cite journal | vauthors = Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hübner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H, Schöler HR | title = Oct4-induced pluripotency in adult neural stem cells | journal = Cell | volume = 136 | issue = 3 | pages = 411–9 | date = Feb 2009 | pmid = 19203577 | doi = 10.1016/j.cell.2009.01.023 }}</ref>
Oct-4 is one of the transcription factors used to create [[induced pluripotent stem cell]]s, together with [[Sox2]],  [[Kruppel-like factors|Klf4]] and often c-[[Myc]] in mouse,<ref>{{cite journal | vauthors = Okita K, Ichisaka T, Yamanaka S | title = Generation of germline-competent induced pluripotent stem cells | journal = Nature | volume = 448 | issue = 7151 | pages = 313–7 | date = Jul 2007 | pmid = 17554338 | doi = 10.1038/nature05934 }}</ref><ref>{{cite journal | vauthors = Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R | title = In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state | journal = Nature | volume = 448 | issue = 7151 | pages = 318–24 | date = Jul 2007 | pmid = 17554336 | doi = 10.1038/nature05944 }}</ref><ref>{{cite journal | vauthors = Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K | title = Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution | journal = Cell Stem Cell | volume = 1 | issue = 1 | pages = 55–70 | date = Jun 2007 | pmid = 18371336 | doi = 10.1016/j.stem.2007.05.014 }}</ref> demonstrating its capacity to induce an embryonic stem cell-like state. These factors are often referred to as "Yamanaka reprogramming factors". This reprogramming effect has also been seen with the [[Thomson reprogramming factors]], reverting human fibroblast cells to iPSCs through Oct-4, along with Sox2, [[Homeobox protein NANOG|Nanog]], and [[Lin28]]. The use of Thomson reprogramming factors avoids the need to overexpress c-Myc, an oncogene.<ref>{{cite journal  |vauthors=Yu J, Vodyanik MA, etal | title = Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells | journal = [[Science (journal)|Science]] | doi = 10.1126/science.1151526 | pmid = 18029452 | year = 2007 | volume = 318 | issue = 5858 | pages = 1917–1920}}</ref>  It was later determined that only two of these four factors, Oct4 and Klf4, were sufficient to reprogram mouse adult neural stem cells.<ref name="pmid18594515">{{cite journal | vauthors = Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR | title = Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors | journal = Nature | volume = 454 | issue = 7204 | pages = 646–50 | date = Jul 2008 | pmid = 18594515 | doi = 10.1038/nature07061 }}</ref>  Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.<ref name="Kim_2009">{{cite journal | vauthors = Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hübner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H, Schöler HR | title = Oct4-induced pluripotency in adult neural stem cells | journal = Cell | volume = 136 | issue = 3 | pages = 411–9 | date = Feb 2009 | pmid = 19203577 | doi = 10.1016/j.cell.2009.01.023 }}</ref>


==In embryonic stem cells==
==In embryonic stem cells==
In in-vitro experiments of murine Embryonic Stem Cells, Oct-4 has often been used as a marker of stemness, as differentiated cells show reduced expression of this marker.
In ''in vitro'' experiments of mouse embryonic stem cells, Oct-4 has often been used as a marker of stemness, as differentiated cells show reduced expression of this marker.


Oct3/4 can both repress and activate the [[Rex1]] promoter. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.<ref name=p758>{{cite journal | vauthors = Ben-Shushan E, Thompson JR, Gudas LJ, Bergman Y | title = Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site | journal = Molecular and Cellular Biology | volume = 18 | issue = 4 | pages = 1866–78 | date = Apr 1998 | pmid = 9528758 | pmc = 121416 | doi=10.1128/mcb.18.4.1866}}</ref> However, in cells that are not actively expressing Oct3/4, an exogenous transfection of Oct3/4 will lead to the activation of Rex1.<ref name=p758/> This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 [[promoter (biology)|promoter]] is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.
Oct3/4 can both repress and activate the [[promoter (biology)|promoter]] of ''[[Rex1]]''. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.<ref name=p758>{{cite journal | vauthors = Ben-Shushan E, Thompson JR, Gudas LJ, Bergman Y | title = Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site | journal = Molecular and Cellular Biology | volume = 18 | issue = 4 | pages = 1866–78 | date = Apr 1998 | pmid = 9528758 | pmc = 121416 | doi=10.1128/mcb.18.4.1866}}</ref> However, in cells that are not actively expressing Oct3/4, exogenous transfection of Oct3/4 will lead to the activation of Rex1.<ref name=p758/> This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.
 
[[CRISPR-Cas9]] knockout of the gene in human embryonic stem cells demonstrated that Oct-4 is essential for the development after fertilisation.<ref>{{cite journal|doi=10.1038/nature24033|pmid=28953884|pmc=5815497|title=Genome editing reveals a role for OCT4 in human embryogenesis|journal=Nature|volume=550|issue=7674|pages=67–73|year=2017|last1=Fogarty|first1=Norah M. E.|last2=McCarthy|first2=Afshan|last3=Snijders|first3=Kirsten E.|last4=Powell|first4=Benjamin E.|last5=Kubikova|first5=Nada|last6=Blakeley|first6=Paul|last7=Lea|first7=Rebecca|last8=Elder|first8=Kay|last9=Wamaitha|first9=Sissy E.|last10=Kim|first10=Daesik|last11=MacIulyte|first11=Valdone|last12=Kleinjung|first12=Jens|last13=Kim|first13=Jin-Soo|last14=Wells|first14=Dagan|last15=Vallier|first15=Ludovic|last16=Bertero|first16=Alessandro|last17=Turner|first17=James M. A.|last18=Niakan|first18=Kathy K.}}</ref>


== In adult stem cells ==
== In adult stem cells ==
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== See also ==
== See also ==
{{colbegin|3}}
{{div col|colwidth=22em}}
*[[Enhancer (genetics)|Enhancer]]  
*[[Enhancer (genetics)|Enhancer]]  
*[[Histone]]  
*[[Histone]]  
*[[Nanog (transcription factor)]]
*[[Pribnow box]]  
*[[Pribnow box]]  
*[[RNA polymerase]]
*[[RNA polymerase]]
*[[Transcription factors]]
*[[Gene regulatory network]]
*[[Gene regulatory network]]
*[[Induced Pluripotent Stem Cell|Induced pluripotent stem cells (iPS) Cells]]
{{div col end}}
{{colend}}


== References ==
== References ==
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* {{cite journal | vauthors = Crouau-Roy B, Amadou C, Bouissou C, Clayton J, Vernet C, Ribouchon MT, Pontarotti P | title = Localization of the OTF3 gene within the human MHC class I region by physical and meiotic mapping | journal = Genomics | volume = 21 | issue = 1 | pages = 241–3 | date = May 1994 | pmid = 8088794 | doi = 10.1006/geno.1994.1249 }}
* {{cite journal | vauthors = Crouau-Roy B, Amadou C, Bouissou C, Clayton J, Vernet C, Ribouchon MT, Pontarotti P | title = Localization of the OTF3 gene within the human MHC class I region by physical and meiotic mapping | journal = Genomics | volume = 21 | issue = 1 | pages = 241–3 | date = May 1994 | pmid = 8088794 | doi = 10.1006/geno.1994.1249 }}
* {{cite journal | vauthors = Guillaudeux T, Mattei MG, Depetris D, Le Bouteiller P, Pontarotti P | title = In situ hybridization localizes the human OTF3 to chromosome 6p21.3-->p22 and OTF3L to 12p13 | journal = Cytogenetics and Cell Genetics | volume = 63 | issue = 4 | pages = 212–4 | year = 1993 | pmid = 8500351 | doi = 10.1159/000133537 }}
* {{cite journal | vauthors = Guillaudeux T, Mattei MG, Depetris D, Le Bouteiller P, Pontarotti P | title = In situ hybridization localizes the human OTF3 to chromosome 6p21.3-->p22 and OTF3L to 12p13 | journal = Cytogenetics and Cell Genetics | volume = 63 | issue = 4 | pages = 212–4 | year = 1993 | pmid = 8500351 | doi = 10.1159/000133537 }}
* {{cite journal | vauthors = Abdel-Rahman B, Fiddler M, Rappolee D, Pergament E | title = Expression of transcription regulating genes in human preimplantation embryos | journal = Human Reproduction | volume = 10 | issue = 10 | pages = 2787–92 | date = Oct 1995 | pmid = 8567814 | doi =  }}
* {{cite journal | vauthors = Abdel-Rahman B, Fiddler M, Rappolee D, Pergament E | title = Expression of transcription regulating genes in human preimplantation embryos | journal = Human Reproduction | volume = 10 | issue = 10 | pages = 2787–92 | date = Oct 1995 | pmid = 8567814 | doi =  10.1093/oxfordjournals.humrep.a135792}}
* {{cite journal | vauthors = Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M | title = Generation and analysis of 280,000 human expressed sequence tags | journal = Genome Research | volume = 6 | issue = 9 | pages = 807–28 | date = Sep 1996 | pmid = 8889549 | doi = 10.1101/gr.6.9.807 }}
* {{cite journal | vauthors = Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M | title = Generation and analysis of 280,000 human expressed sequence tags | journal = Genome Research | volume = 6 | issue = 9 | pages = 807–28 | date = Sep 1996 | pmid = 8889549 | doi = 10.1101/gr.6.9.807 }}
* {{cite journal | vauthors = Inamoto S, Segil N, Pan ZQ, Kimura M, Roeder RG | title = The cyclin-dependent kinase-activating kinase (CAK) assembly factor, MAT1, targets and enhances CAK activity on the POU domains of octamer transcription factors | journal = The Journal of Biological Chemistry | volume = 272 | issue = 47 | pages = 29852–8 | date = Nov 1997 | pmid = 9368058 | doi = 10.1074/jbc.272.47.29852 }}
* {{cite journal | vauthors = Inamoto S, Segil N, Pan ZQ, Kimura M, Roeder RG | title = The cyclin-dependent kinase-activating kinase (CAK) assembly factor, MAT1, targets and enhances CAK activity on the POU domains of octamer transcription factors | journal = The Journal of Biological Chemistry | volume = 272 | issue = 47 | pages = 29852–8 | date = Nov 1997 | pmid = 9368058 | doi = 10.1074/jbc.272.47.29852 }}

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
View/Edit Human

Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the POU5F1 gene.[1] Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells.[2] As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.[3]

Oct-4 is a member of the octamer transcription factor family, so named because they bind the octameric (8-unit) DNA nucleotide sequence "ATTTGCAT".[4]

Expression and function

Oct-4 transcription factor is initially active as a maternal factor in the oocyte and remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors.[5] Gene knockdown of Oct-4 promotes differentiation, demonstrating a role for these factors in human embryonic stem cell self-renewal.[6] Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together.[7]

Mouse embryos that are Oct-4 deficient or have low expression levels of Oct-4 fail to form the inner cell mass, lose pluripotency, and differentiate into trophectoderm. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.

Orthologs

Orthologs of Oct-4 in humans and other species include:

Species Entrez GeneID Chromosome Location RefSeq (mRNA) RefSeq (protein)
Mus musculus (mouse) 18999 17,17 B1; 17 19.23 cM NC_000083.4, 35114104..35118822 (Plus Strand) NM_013633.1 NP_038661.1
Homo sapiens (human) 5460 6, 6p21.31 NC_000006.10, 31246432-31240107 (Minus Strand) NM_002701.3 NP_002692.2 (full length isoform)
NP_002692.1 (N-terminal truncated isoform)
Rattus norvegicus (rat) 294562 20 NW_001084776, 650467-655015 (Minus strand) NM_001009178 NP_001009178
Danio rerio (zebrafish) 303333 21 NC_007127.1, 27995548-28000317 (Minus strand) NM_131112 NP_571187

Structure

Oct-4 contains the following protein domains:

Domain Description Length (AA)
POU domain Found in Pit-Oct-Unc transcription factors 75
Homeodomain DNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homodimers and/or heterodimers in a sequence-specific manner. 59

Implications in disease

Oct-4 has been implicated in tumorigenesis of adult germ cells. Ectopic expression of the factor in adult mice has been found to cause the formation of dysplastic lesions of the skin and intestine. The intestinal dysplasia resulted from an increase in progenitor cell population and the upregulation of β-catenin transcription through the inhibition of cellular differentiation.[8]

Pluripotency in embryo development

Animal model

In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem cells to determine requirements for Oct-4 in the maintenance of developmental potency.[3] Although transcriptional determination has often been considered as a binary on-off control system, they found that the precise level of Oct-4 governs 3 distinct fates of ES cells. An increase in expression of less than 2-fold causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down-regulation induces divergent developmental programs. Changes to Oct-4 levels do not independently promote differentiation, but are also controlled by levels of Sox2. A decrease in Sox2 accompanies increased levels of Oct-4 to promote a mesendodermal fate, with Oct-4 actively inhibiting ectodermal differentiation. Repressed Oct-4 levels that lead to ectodermal differentiation are accompanied by an increase in Sox2, which effectively inhibits mesendodermal differentiation.[9] Niwa et al. suggested that their findings established a role for Oct-4 as a master regulator of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyzes.

The transcription factors Oct-4, Sox2 and Nanog are part of a complex regulatory network with Oct-4 and Sox2 capable of directly regulating Nanog by binding to its promoter, and are essential for maintaining the self-renewing undifferentiated state of the inner cell mass of the blastocyst, embryonic stem cell lines (which are cell lines derived from the inner cell mass), and induced pluripotent stem cells.[7] While differential up- and down-regulation of Oct-4 and Sox2 has been shown to promote differentiation, down-regulation of Nanog must occur for differentiation to proceed.[9]

Role in reprogramming

Oct-4 is one of the transcription factors used to create induced pluripotent stem cells, together with Sox2, Klf4 and often c-Myc in mouse,[10][11][12] demonstrating its capacity to induce an embryonic stem cell-like state. These factors are often referred to as "Yamanaka reprogramming factors". This reprogramming effect has also been seen with the Thomson reprogramming factors, reverting human fibroblast cells to iPSCs through Oct-4, along with Sox2, Nanog, and Lin28. The use of Thomson reprogramming factors avoids the need to overexpress c-Myc, an oncogene.[13] It was later determined that only two of these four factors, Oct4 and Klf4, were sufficient to reprogram mouse adult neural stem cells.[14] Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.[15]

In embryonic stem cells

In in vitro experiments of mouse embryonic stem cells, Oct-4 has often been used as a marker of stemness, as differentiated cells show reduced expression of this marker.

Oct3/4 can both repress and activate the promoter of Rex1. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.[16] However, in cells that are not actively expressing Oct3/4, exogenous transfection of Oct3/4 will lead to the activation of Rex1.[16] This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.

CRISPR-Cas9 knockout of the gene in human embryonic stem cells demonstrated that Oct-4 is essential for the development after fertilisation.[17]

In adult stem cells

Several studies suggest a role for Oct-4 in sustaining self-renewal capacity of adult somatic stem cells (i.e. stem cells from epithelium, bone marrow, liver, etc.).[18] Other scientists have produced evidence to the contrary,[19] and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal,[20] and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression.[21] Oct-4 has also been implicated as a marker of cancer stem cells.[22][23]

See also

References

  1. Takeda J, Seino S, Bell GI (Sep 1992). "Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues". Nucleic Acids Research. 20 (17): 4613–20. doi:10.1093/nar/20.17.4613. PMC 334192. PMID 1408763.
  2. Young Lab- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells Archived 2009-06-28 at the Wayback Machine. at MIT
  3. 3.0 3.1 Niwa H, Miyazaki J, Smith AG (Apr 2000). "Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells". Nature Genetics. 24 (4): 372–6. doi:10.1038/74199. PMID 10742100.
  4. Petryniak B, Staudt LM, Postema CE, McCormack WT, Thompson CB (Feb 1990). "Characterization of chicken octamer-binding proteins demonstrates that POU domain-containing homeobox transcription factors have been highly conserved during vertebrate evolution". Proceedings of the National Academy of Sciences of the United States of America. 87 (3): 1099–103. doi:10.1073/pnas.87.3.1099. PMC 53418. PMID 1967834.
  5. Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW (May 2003). "POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors". Cancer Research. 63 (9): 2244–50. PMID 12727846.
  6. Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ (Mar 2005). "High-efficiency RNA interference in human embryonic stem cells". Stem Cells. 23 (3): 299–305. doi:10.1634/stemcells.2004-0252. PMID 15749924.
  7. 7.0 7.1 Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P (Jul 2005). "Transcriptional regulation of nanog by OCT4 and SOX2". The Journal of Biological Chemistry. 280 (26): 24731–7. doi:10.1074/jbc.M502573200. PMID 15860457.
  8. Hochedlinger K, Yamada Y, Beard C, Jaenisch R (May 2005). "Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues". Cell. 121 (3): 465–77. doi:10.1016/j.cell.2005.02.018. PMID 15882627.
  9. 9.0 9.1 Thomson M, Liu SJ, Zou LN, Smith Z, Meissner A, Ramanathan S (June 2011). "Pluripotency factors in embryonic stem cells regulate differentiation into germ layers". Cell. 145 (6): 875–89. doi:10.1016/j.cell.2011.05.017. PMID 21663792.
  10. Okita K, Ichisaka T, Yamanaka S (Jul 2007). "Generation of germline-competent induced pluripotent stem cells". Nature. 448 (7151): 313–7. doi:10.1038/nature05934. PMID 17554338.
  11. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (Jul 2007). "In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state". Nature. 448 (7151): 318–24. doi:10.1038/nature05944. PMID 17554336.
  12. Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K (Jun 2007). "Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution". Cell Stem Cell. 1 (1): 55–70. doi:10.1016/j.stem.2007.05.014. PMID 18371336.
  13. Yu J, Vodyanik MA, et al. (2007). "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells". Science. 318 (5858): 1917–1920. doi:10.1126/science.1151526. PMID 18029452.
  14. Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR (Jul 2008). "Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors". Nature. 454 (7204): 646–50. doi:10.1038/nature07061. PMID 18594515.
  15. Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hübner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H, Schöler HR (Feb 2009). "Oct4-induced pluripotency in adult neural stem cells". Cell. 136 (3): 411–9. doi:10.1016/j.cell.2009.01.023. PMID 19203577.
  16. 16.0 16.1 Ben-Shushan E, Thompson JR, Gudas LJ, Bergman Y (Apr 1998). "Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site". Molecular and Cellular Biology. 18 (4): 1866–78. doi:10.1128/mcb.18.4.1866. PMC 121416. PMID 9528758.
  17. Fogarty, Norah M. E.; McCarthy, Afshan; Snijders, Kirsten E.; Powell, Benjamin E.; Kubikova, Nada; Blakeley, Paul; Lea, Rebecca; Elder, Kay; Wamaitha, Sissy E.; Kim, Daesik; MacIulyte, Valdone; Kleinjung, Jens; Kim, Jin-Soo; Wells, Dagan; Vallier, Ludovic; Bertero, Alessandro; Turner, James M. A.; Niakan, Kathy K. (2017). "Genome editing reveals a role for OCT4 in human embryogenesis". Nature. 550 (7674): 67–73. doi:10.1038/nature24033. PMC 5815497. PMID 28953884.
  18. For example:
  19. Lengner CJ, Camargo FD, Hochedlinger K, Welstead GG, Zaidi S, Gokhale S, Scholer HR, Tomilin A, Jaenisch R (Oct 2007). "Oct4 expression is not required for mouse somatic stem cell self-renewal". Cell Stem Cell. 1 (4): 403–15. doi:10.1016/j.stem.2007.07.020. PMC 2151746. PMID 18159219.
  20. Lengner CJ, Welstead GG, Jaenisch R (Mar 2008). "The pluripotency regulator Oct4: a role in somatic stem cells?". Cell Cycle. 7 (6): 725–8. doi:10.4161/cc.7.6.5573. PMID 18239456.
  21. Zangrossi S, Marabese M, Broggini M, Giordano R, D'Erasmo M, Montelatici E, Intini D, Neri A, Pesce M, Rebulla P, Lazzari L (Jul 2007). "Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker". Stem Cells. 25 (7): 1675–80. doi:10.1634/stemcells.2006-0611. PMID 17379765.
  22. Kim RJ, Nam JS (Jun 2011). "OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer". Laboratory Animal Research. 27 (2): 147–52. doi:10.5625/lar.2011.27.2.147. PMC 3145994. PMID 21826175.
  23. Atlasi Y, Mowla SJ, Ziaee SA, Bahrami AR (Apr 2007). "OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer". International Journal of Cancer. 120 (7): 1598–602. doi:10.1002/ijc.22508. PMID 17205510.

Further reading

External links