IRF8: Difference between revisions

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{{Infobox_gene}}
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'''Interferon regulatory factor 8''' (IRF8) also known as '''interferon consensus sequence-binding protein''' (ICSBP), is a [[protein]] that in humans is encoded by the ''IRF8'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: IRF8 interferon regulatory factor 8| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3394| accessdate = }}</ref><ref name="pmid1460054">{{cite journal | vauthors = Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ | title = Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes | journal = J. Biol. Chem. | volume = 267 | issue = 35 | pages = 25589–96 | date = December 1992 | pmid = 1460054 | doi =  | url = http://www.jbc.org/cgi/reprint/267/35/25589 }}</ref><ref name="pmid11997525">{{cite journal | vauthors = Nehyba J, Hrdlicková R, Burnside J, Bose HR | title = A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein | journal = Mol. Cell. Biol. | volume = 22 | issue = 11 | pages = 3942–57 | date = June 2002 | pmid = 11997525 | pmc = 133824 | doi = 10.1128/MCB.22.11.3942-3957.2002 }}</ref> IRF8 is a [[transcription factor]] that plays critical roles in the regulation of lineage commitment and in [[myeloid]] [[Cell (biology)|cell]] maturation including the decision for a common myeloid progenitor (CMP) to [[Cellular differentiation|differentiate]] into a [[monocyte]] precursor cell.
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| update_protein_box = yes
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== Function ==
{{GNF_Protein_box
[[Interferon Consensus Sequence-binding protein]] (ICSBP) is a [[transcription factor]] of the [[interferon]] regulatory factor ([[Interferon regulatory factors|IRF]]) family. Proteins of this family are composed of a conserved [[DNA-binding domain]] in the [[N-terminus|N-terminal]] region and a divergent [[C-terminus|C-terminal]] region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated [[response element]] (ISRE) and regulate expression of genes stimulated by type I IFNs, namely [[Interferon type I#IFN-.CE.B1|IFN-α]] and [[Interferon type I#IFN-.CE.B2|IFN-β]]. IRF family proteins also control expression of IFN-α and IFN-β-regulated genes that are induced by viral infection.<ref name="entrez"/>
| image =
| image_source =
| PDB =  
| Name = Interferon regulatory factor 8
| HGNCid = 5358
| Symbol = IRF8
| AltSymbols =; H-ICSBP; ICSBP; ICSBP1; IRF-8
| OMIM = 601565
| ECnumber = 
| Homologene = 1629
| MGIid = 96395
| GeneAtlas_image1 = PBB_GE_IRF8_204057_at_tn.png
| Function = {{GNF_GO|id=GO:0003705 |text = RNA polymerase II transcription factor activity, enhancer binding}}
| Component = {{GNF_GO|id=GO:0005622 |text = intracellular}} {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0000122 |text = negative regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006955 |text = immune response}} {{GNF_GO|id=GO:0030099 |text = myeloid cell differentiation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3394
    | Hs_Ensembl = ENSG00000140968
    | Hs_RefseqProtein = NP_002154
    | Hs_RefseqmRNA = NM_002163
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 16
    | Hs_GenLoc_start = 84490275
    | Hs_GenLoc_end = 84513710
    | Hs_Uniprot = Q02556
    | Mm_EntrezGene = 15900
    | Mm_Ensembl = ENSMUSG00000041515
    | Mm_RefseqmRNA = NM_008320
    | Mm_RefseqProtein = NP_032346
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 8
    | Mm_GenLoc_start = 123622335
    | Mm_GenLoc_end = 123642667
    | Mm_Uniprot = Q3TZQ3
  }}
}}
'''Interferon regulatory factor 8''', also known as '''IRF8''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: IRF8 interferon regulatory factor 8| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3394| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Knockout studies ==
{{PBB_Summary
IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP [[knockout mouse|knockout]] (KO) mice, as revealed by lack of CD11c<sup>low</sup>B220<sup>+</sup>Ly6C<sup>+</sup>CD11b<sup>−</sup> cells. In parallel, CD11c<sup>+</sup> cells isolated from ICSBP KO spleens were unable to produce type I IFNs in response to viral stimulation. ICSBP KO mice also displayed a marked reduction of the DC subset expressing the CD8alpha marker (CD8alpha<sup>+</sup> DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP-deficient CD8alpha<sup>+</sup> DCs exhibited a markedly impaired phenotype when compared with WT DCs. They expressed very low levels of costimulatory molecules (intercellular adhesion molecule [[ICAM1]], [[CD40]], [[CD80]], [[CD86]]) and of the T cell area-homing chemokine receptor [[CCR7]].<ref name="pmid11846985">{{cite journal | vauthors = Tamura T, Ozato K | title = ICSBP/IRF-8: its regulatory roles in the development of myeloid cells | journal = J. Interferon Cytokine Res. | volume = 22 | issue = 1 | pages = 145–52 | date = January 2002 | pmid = 11846985 | doi = 10.1089/107999002753452755 }}</ref>
| section_title =  
| summary_text = Interferon consensus sequence-binding protein (ICSBP) is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-alpha and IFN-beta. IRF family proteins also control expression of IFN-alpha and IFN-beta-regulated genes that are induced by viral infection.<ref name="entrez">{{cite web | title = Entrez Gene: IRF8 interferon regulatory factor 8| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3394| accessdate = }}</ref>
}}


==See also==
== Clinical significance ==
In myeloid cells, IRF8 regulates the expression of [[Bcl-2-associated X protein|Bax]] and [[Fas receptor|Fas]] to regulate [[apoptosis]].<ref name="pmid21949018">{{cite journal | vauthors = Yang J, Hu X, Zimmerman M, Torres CM, Yang D, Smith SB, Liu K | title = Cutting edge: IRF8 regulates Bax transcription in vivo in primary myeloid cells | journal = J. Immunol. | volume = 187 | issue = 9 | pages = 4426–30 | date = November 2011 | pmid = 21949018 | pmc = 3197864 | doi = 10.4049/jimmunol.1101034 }}</ref> In [[chronic myelogenous leukemia]] (CML), IRF8 regulates acid [[ceramidase]] to mediate CML apoptosis.<ref name="pmid21487040">{{cite journal | vauthors = Hu X, Yang D, Zimmerman M, Liu F, Yang J, Kannan S, Burchert A, Szulc Z, Bielawska A, Ozato K, Bhalla K, Liu K | title = IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia | journal = Cancer Res. | volume = 71 | issue = 8 | pages = 2882–91 | date = April 2011 | pmid = 21487040 | pmc = 3078194 | doi = 10.1158/0008-5472.CAN-10-2493 }}</ref>
 
IRF8 is highly expressed in myeloid cells and was originally identified in as a critical lineage-specific transcription factor for myeloid cell differentiation,<ref name="pmid8861914">{{cite journal | vauthors = Holtschke T, Löhler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring JF, Bachmann MF, Zinkernagel RM, Morse HC, Ozato K, Horak I | title = Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene | journal = Cell | volume = 87 | issue = 2 | pages = 307–17 | date = October 1996 | pmid = 8861914 | doi = 10.1016/S0092-8674(00)81348-3 }}</ref> recent studies, however, have shown that IRF8 is also constitutively expressed in non-[[hematopoietic]] cancer cells, albeit at a lower level. Furthermore, IRF8 can also be up-regulated by IFN-γ in non-hemotopoietic cells. IRF8 mediates the expression of Fas, Bax, [[CFLAR|FLIP]], [[Janus kinase 1|Jak1]] and [[STAT1]] to mediate apoptosis in non-hemotopoietic cancer cells.<ref name="pmid19155307">{{cite journal | vauthors = Yang D, Wang S, Brooks C, Dong Z, Schoenlein PV, Kumar V, Ouyang X, Xiong H, Lahat G, Hayes-Jordan A, Lazar A, Pollock R, Lev D, Liu K | title = IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression | journal = Cancer Res. | volume = 69 | issue = 3 | pages = 1080–8 | date = February 2009 | pmid = 19155307 | pmc = 2633427 | doi = 10.1158/0008-5472.CAN-08-2520 }}</ref><ref name="pmid17878376">{{cite journal | vauthors = Yang D, Thangaraju M, Browning DD, Dong Z, Korchin B, Lev DC, Ganapathy V, Liu K | title = IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression | journal = J. Immunol. | volume = 179 | issue = 7 | pages = 4775–82 | date = October 2007 | pmid = 17878376 | doi = 10.4049/jimmunol.179.7.4775 }}</ref><ref name="pmid17409439">{{cite journal | vauthors = Yang D, Thangaraju M, Greeneltch K, Browning DD, Schoenlein PV, Tamura T, Ozato K, Ganapathy V, Abrams SI, Liu K | title = Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells | journal = Cancer Res. | volume = 67 | issue = 7 | pages = 3301–9 | date = April 2007 | pmid = 17409439 | doi = 10.1158/0008-5472.CAN-06-4068 }}</ref>
 
Analysis of human cancer genomics database revealed that IRF8 is not significantly focally amplified across the entire dataset of 3131 tumors, but is significantly focally deleted across the entire dataset of 3131 tumors, suggesting that IRF8 is potentially a [[tumor suppressor]] in humans.<ref name="urlTumorscape">{{cite web | url = http://www.broadinstitute.org/tumorscape/pages/portalHome.jsf | title = Tumorscape | format = | work = | publisher = The Broad Institute }}</ref> Molecular analysis indicated that the IRF8 gene promoter is hypermethylated in human [[colon carcinoma]] cells,<ref name="pmid17409439"/><ref name="pmid19074829">{{cite journal | vauthors = McGough JM, Yang D, Huang S, Georgi D, Hewitt SM, Röcken C, Tänzer M, Ebert MP, Liu K | title = DNA methylation represses IFN-gamma-induced and signal transducer and activator of transcription 1-mediated IFN regulatory factor 8 activation in colon carcinoma cells | journal = Mol. Cancer Res. | volume = 6 | issue = 12 | pages = 1841–51 | date = December 2008 | pmid = 19074829 | pmc = 2605678 | doi = 10.1158/1541-7786.MCR-08-0280 }}</ref> suggesting that these cells might use DNA methylation to silence IRF8 expression to advance the disease.
 
== Interactions ==
 
IRF8 has been shown to [[Protein-protein interaction|interact]] with [[IRF1]]<ref name="pmid9742224">{{cite journal | vauthors = Schaper F, Kirchhoff S, Posern G, Köster M, Oumard A, Sharf R, Levi BZ, Hauser H | title = Functional domains of interferon regulatory factor I (IRF-1) | journal = Biochem. J. | volume = 335 | issue = 1 | pages = 147–57 | date = October 1998 | pmid = 9742224 | pmc = 1219763 | doi =  }}</ref><ref name="pmid7768900">{{cite journal | vauthors = Sharf R, Azriel A, Lejbkowicz F, Winograd SS, Ehrlich R, Levi BZ | title = Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors | journal = J. Biol. Chem. | volume = 270 | issue = 22 | pages = 13063–9 | date = June 1995 | pmid = 7768900 | doi = 10.1074/jbc.270.22.13063 }}</ref> and [[COPS2]].<ref name="pmid10991940">{{cite journal | vauthors = Cohen H, Azriel A, Cohen T, Meraro D, Hashmueli S, Bech-Otschir D, Kraft R, Dubiel W, Levi BZ | title = Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome | journal = J. Biol. Chem. | volume = 275 | issue = 50 | pages = 39081–9 | date = December 2000 | pmid = 10991940 | doi = 10.1074/jbc.M004900200 }}</ref>
 
== See also ==
* [[Interferon regulatory factors]]
* [[Interferon regulatory factors]]


==References==
== References ==
{{reflist|2}}
{{reflist|35em}}
 
==Illustrations==
[[File:IRF8 in host response.png|350px|thumb|center]]


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ | title = Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes. | journal = J. Biol. Chem. | volume = 267 | issue = 35 | pages = 25589–96 | year = 1993 | pmid = 1460054 | doi =  }}
| citations =
* {{cite journal | vauthors = Sharf R, Azriel A, Lejbkowicz F, Winograd SS, Ehrlich R, Levi BZ | title = Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. | journal = J. Biol. Chem. | volume = 270 | issue = 22 | pages = 13063–9 | year = 1995 | pmid = 7768900 | doi = 10.1074/jbc.270.22.13063 }}
*{{cite journal | author=Weisz A, Marx P, Sharf R, ''et al.'' |title=Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes. |journal=J. Biol. Chem. |volume=267 |issue= 35 |pages= 25589-96 |year= 1993 |pmid= 1460054 |doi=  }}
* {{cite journal | vauthors = Holtschke T, Löhler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring JF, Bachmann MF, Zinkernagel RM, Morse HC, Ozato K, Horak I | title = Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. | journal = Cell | volume = 87 | issue = 2 | pages = 307–17 | year = 1996 | pmid = 8861914 | doi = 10.1016/S0092-8674(00)81348-3 }}
*{{cite journal | author=Sharf R, Azriel A, Lejbkowicz F, ''et al.'' |title=Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. |journal=J. Biol. Chem. |volume=270 |issue= 22 |pages= 13063-9 |year= 1995 |pmid= 7768900 |doi= }}
* {{cite journal | vauthors = Schaper F, Kirchhoff S, Posern G, Köster M, Oumard A, Sharf R, Levi BZ, Hauser H | title = Functional domains of interferon regulatory factor I (IRF-1). | journal = Biochem. J. | volume = 335 | issue = 1 | pages = 147–57 | year = 1998 | pmid = 9742224 | pmc = 1219763 | doi =  }}
*{{cite journal | author=Holtschke T, Löhler J, Kanno Y, ''et al.'' |title=Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. |journal=Cell |volume=87 |issue= 2 |pages= 307-17 |year= 1996 |pmid= 8861914 |doi= }}
* {{cite journal | vauthors = Li W, Nagineni CN, Ge H, Efiok B, Chepelinsky AB, Egwuagu CE | title = Interferon consensus sequence-binding protein is constitutively expressed and differentially regulated in the ocular lens. | journal = J. Biol. Chem. | volume = 274 | issue = 14 | pages = 9686–91 | year = 1999 | pmid = 10092656 | doi = 10.1074/jbc.274.14.9686 }}
*{{cite journal | author=Schaper F, Kirchhoff S, Posern G, ''et al.'' |title=Functional domains of interferon regulatory factor I (IRF-1). |journal=Biochem. J. |volume=335 ( Pt 1) |issue= |pages= 147-57 |year= 1998 |pmid= 9742224 |doi=  }}
* {{cite journal | vauthors = Li W, Nagineni CN, Hooks JJ, Chepelinsky AB, Egwuagu CE | title = Interferon-gamma signaling in human retinal pigment epithelial cells mediated by STAT1, ICSBP, and IRF-1 transcription factors. | journal = Invest. Ophthalmol. Vis. Sci. | volume = 40 | issue = 5 | pages = 976–82 | year = 1999 | pmid = 10102295 | doi =  }}
*{{cite journal | author=Li W, Nagineni CN, Ge H, ''et al.'' |title=Interferon consensus sequence-binding protein is constitutively expressed and differentially regulated in the ocular lens. |journal=J. Biol. Chem. |volume=274 |issue= 14 |pages= 9686-91 |year= 1999 |pmid= 10092656 |doi= }}
* {{cite journal | vauthors = Rehli M, Poltorak A, Schwarzfischer L, Krause SW, Andreesen R, Beutler B | title = PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene. | journal = J. Biol. Chem. | volume = 275 | issue = 13 | pages = 9773–81 | year = 2000 | pmid = 10734131 | doi = 10.1074/jbc.275.13.9773 }}
*{{cite journal | author=Li W, Nagineni CN, Hooks JJ, ''et al.'' |title=Interferon-gamma signaling in human retinal pigment epithelial cells mediated by STAT1, ICSBP, and IRF-1 transcription factors. |journal=Invest. Ophthalmol. Vis. Sci. |volume=40 |issue= 5 |pages= 976-82 |year= 1999 |pmid= 10102295 |doi=  }}
* {{cite journal | vauthors = Cohen H, Azriel A, Cohen T, Meraro D, Hashmueli S, Bech-Otschir D, Kraft R, Dubiel W, Levi BZ | title = Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome. | journal = J. Biol. Chem. | volume = 275 | issue = 50 | pages = 39081–9 | year = 2001 | pmid = 10991940 | doi = 10.1074/jbc.M004900200 }}
*{{cite journal | author=Rehli M, Poltorak A, Schwarzfischer L, ''et al.'' |title=PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene. |journal=J. Biol. Chem. |volume=275 |issue= 13 |pages= 9773-81 |year= 2000 |pmid= 10734131 |doi= }}
* {{cite journal | vauthors = Nehyba J, Hrdlicková R, Burnside J, Bose HR | title = A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein. | journal = Mol. Cell. Biol. | volume = 22 | issue = 11 | pages = 3942–57 | year = 2002 | pmid = 11997525 | pmc = 133824 | doi = 10.1128/MCB.22.11.3942-3957.2002 }}
*{{cite journal | author=Cohen H, Azriel A, Cohen T, ''et al.'' |title=Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome. |journal=J. Biol. Chem. |volume=275 |issue= 50 |pages= 39081-9 |year= 2001 |pmid= 10991940 |doi= 10.1074/jbc.M004900200 }}
* {{cite journal | vauthors = Zhu C, Saberwal G, Lu Y, Platanias LC, Eklund EA | title = The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1. | journal = J. Biol. Chem. | volume = 279 | issue = 49 | pages = 50874–85 | year = 2005 | pmid = 15371411 | doi = 10.1074/jbc.M405736200 }}
*{{cite journal | author=Nehyba J, Hrdlicková R, Burnside J, Bose HR |title=A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein. |journal=Mol. Cell. Biol. |volume=22 |issue= 11 |pages= 3942-57 |year= 2002 |pmid= 11997525 |doi= }}
* {{cite journal | vauthors = Liu J, Guan X, Tamura T, Ozato K, Ma X | title = Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein. | journal = J. Biol. Chem. | volume = 279 | issue = 53 | pages = 55609–17 | year = 2005 | pmid = 15489234 | doi = 10.1074/jbc.M406565200 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, Shinjo F, Liu Y, Dembowy J, Taylor IW, Luga V, Przulj N, Robinson M, Suzuki H, Hayashizaki Y, Jurisica I, Wrana JL | title = High-throughput mapping of a dynamic signaling network in mammalian cells. | journal = Science | volume = 307 | issue = 5715 | pages = 1621–5 | year = 2005 | pmid = 15761153 | doi = 10.1126/science.1105776 }}
*{{cite journal | author=Zhu C, Saberwal G, Lu Y, ''et al.'' |title=The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1. |journal=J. Biol. Chem. |volume=279 |issue= 49 |pages= 50874-85 |year= 2005 |pmid= 15371411 |doi= 10.1074/jbc.M405736200 }}
* {{cite journal | vauthors = Xiong H, Li H, Kong HJ, Chen Y, Zhao J, Xiong S, Huang B, Gu H, Mayer L, Ozato K, Unkeless JC | title = Ubiquitin-dependent degradation of interferon regulatory factor-8 mediated by Cbl down-regulates interleukin-12 expression. | journal = J. Biol. Chem. | volume = 280 | issue = 25 | pages = 23531–9 | year = 2005 | pmid = 15837792 | doi = 10.1074/jbc.M414296200 }}
*{{cite journal | author=Liu J, Guan X, Tamura T, ''et al.'' |title=Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein. |journal=J. Biol. Chem. |volume=279 |issue= 53 |pages= 55609-17 |year= 2005 |pmid= 15489234 |doi= 10.1074/jbc.M406565200 }}
* {{cite journal | vauthors = Zhao J, Kong HJ, Li H, Huang B, Yang M, Zhu C, Bogunovic M, Zheng F, Mayer L, Ozato K, Unkeless J, Xiong H | title = IRF-8/interferon (IFN) consensus sequence-binding protein is involved in Toll-like receptor (TLR) signaling and contributes to the cross-talk between TLR and IFN-gamma signaling pathways. | journal = J. Biol. Chem. | volume = 281 | issue = 15 | pages = 10073–80 | year = 2006 | pmid = 16484229 | doi = 10.1074/jbc.M507788200 }}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
* {{cite journal | vauthors = Huang W, Saberwal G, Horvath E, Zhu C, Lindsey S, Eklund EA | title = Leukemia-associated, constitutively active mutants of SHP2 protein tyrosine phosphatase inhibit NF1 transcriptional activation by the interferon consensus sequence binding protein. | journal = Mol. Cell. Biol. | volume = 26 | issue = 17 | pages = 6311–32 | year = 2006 | pmid = 16914719 | pmc = 1592828 | doi = 10.1128/MCB.00036-06 }}
*{{cite journal | author=Barrios-Rodiles M, Brown KR, Ozdamar B, ''et al.'' |title=High-throughput mapping of a dynamic signaling network in mammalian cells. |journal=Science |volume=307 |issue= 5715 |pages= 1621-5 |year= 2005 |pmid= 15761153 |doi= 10.1126/science.1105776 }}
* {{cite journal | vauthors = Dimberg A, Kårehed K, Nilsson K, Oberg F | title = Inhibition of monocytic differentiation by phosphorylation-deficient Stat1 is associated with impaired expression of Stat2, ICSBP/IRF8 and C/EBPepsilon. | journal = Scand. J. Immunol. | volume = 64 | issue = 3 | pages = 271–9 | year = 2006 | pmid = 16918696 | doi = 10.1111/j.1365-3083.2006.01827.x }}
*{{cite journal | author=Xiong H, Li H, Kong HJ, ''et al.'' |title=Ubiquitin-dependent degradation of interferon regulatory factor-8 mediated by Cbl down-regulates interleukin-12 expression. |journal=J. Biol. Chem. |volume=280 |issue= 25 |pages= 23531-9 |year= 2005 |pmid= 15837792 |doi= 10.1074/jbc.M414296200 }}
* {{cite journal | vauthors = Leonard D, Svenungsson E, Sandling JK, Berggren O, Jönsen A, Bengtsson C, Wang C, Jensen-Urstad K, Granstam SO, Bengtsson AA, Gustafsson JT, Gunnarsson I, Rantapää-Dahlqvist S, Nordmark G, Eloranta ML, Syvänen AC, Rönnblom L | title = Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated with Interferon Regulatory Factor 8 Gene Variants | journal = Circ. Cardiovasc. Genet. | volume = 6 | issue = 3 | pages = 255–63 | year = 2013 | pmid = 23661672 | doi = 10.1161/CIRCGENETICS.113.000044 }}
*{{cite journal | author=Zhao J, Kong HJ, Li H, ''et al.'' |title=IRF-8/interferon (IFN) consensus sequence-binding protein is involved in Toll-like receptor (TLR) signaling and contributes to the cross-talk between TLR and IFN-gamma signaling pathways. |journal=J. Biol. Chem. |volume=281 |issue= 15 |pages= 10073-80 |year= 2006 |pmid= 16484229 |doi= 10.1074/jbc.M507788200 }}
* {{cite journal | vauthors = Peng YB, Yerle M, Liu B | title = Mapping of nine porcine interferon regulatory factor genes. | journal = Anim. Genet. | volume = 37 | issue = 6 | pages = 600–1 | year = 2007 | pmid = 17121613 | doi = 10.1111/j.1365-2052.2006.01525.x }}
*{{cite journal | author=Huang W, Saberwal G, Horvath E, ''et al.'' |title=Leukemia-associated, constitutively active mutants of SHP2 protein tyrosine phosphatase inhibit NF1 transcriptional activation by the interferon consensus sequence binding protein. |journal=Mol. Cell. Biol. |volume=26 |issue= 17 |pages= 6311-32 |year= 2006 |pmid= 16914719 |doi= 10.1128/MCB.00036-06 }}
* {{cite journal | vauthors = Huang W, Horvath E, Eklund EA | title = PU.1, interferon regulatory factor (IRF) 2, and the interferon consensus sequence-binding protein (ICSBP/IRF8) cooperate to activate NF1 transcription in differentiating myeloid cells. | journal = J. Biol. Chem. | volume = 282 | issue = 9 | pages = 6629–43 | year = 2007 | pmid = 17200120 | doi = 10.1074/jbc.M607760200 }}
*{{cite journal | author=Dimberg A, Kårehed K, Nilsson K, Oberg F |title=Inhibition of monocytic differentiation by phosphorylation-deficient Stat1 is associated with impaired expression of Stat2, ICSBP/IRF8 and C/EBPepsilon. |journal=Scand. J. Immunol. |volume=64 |issue= 3 |pages= 271-9 |year= 2006 |pmid= 16918696 |doi= 10.1111/j.1365-3083.2006.01827.x }}
* {{cite journal | vauthors = Mattei F, Schiavoni G, Borghi P, Venditti M, Canini I, Sestili P, Pietraforte I, Morse HC, Ramoni C, Belardelli F, Gabriele L | title = ICSBP/IRF-8 differentially regulates antigen uptake during dendritic-cell development and affects antigen presentation to CD4+ T cells. | journal = Blood | volume = 108 | issue = 2 | pages = 609–617 | year = 2006 | pmid = 16569763 | doi = 10.1182/blood-2005-11-4490 }}
*{{cite journal | author=Peng YB, Yerle M, Liu B |title=Mapping of nine porcine interferon regulatory factor genes. |journal=Anim. Genet. |volume=37 |issue= 6 |pages= 600-1 |year= 2007 |pmid= 17121613 |doi= 10.1111/j.1365-2052.2006.01525.x }}
* {{cite journal | vauthors = Schiavoni G, Mattei F, Sestili P, Borghi P, Venditti M, Morse HC, Belardelli F, Gabriele L | title = ICSBP is essential for the development of mouse type I interferon-producing cells and for the generation and activation of CD8alpha(+) dendritic cells. | journal = J. Exp. Med. | volume = 196 | issue = 11 | pages = 1415–1425 | year = 2002 | pmid = 12461077 | pmc = 2194263 | doi = 10.1084/jem.20021263 }}
*{{cite journal | author=Huang W, Horvath E, Eklund EA |title=PU.1, interferon regulatory factor (IRF) 2, and the interferon consensus sequence-binding protein (ICSBP/IRF8) cooperate to activate NF1 transcription in differentiating myeloid cells. |journal=J. Biol. Chem. |volume=282 |issue= 9 |pages= 6629-43 |year= 2007 |pmid= 17200120 |doi= 10.1074/jbc.M607760200 }}
}}
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Latest revision as of 00:04, 1 September 2017

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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View/Edit Human

Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the IRF8 gene.[1][2][3] IRF8 is a transcription factor that plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a monocyte precursor cell.

Function

Interferon Consensus Sequence-binding protein (ICSBP) is a transcription factor of the interferon regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-α and IFN-β. IRF family proteins also control expression of IFN-α and IFN-β-regulated genes that are induced by viral infection.[1]

Knockout studies

IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP knockout (KO) mice, as revealed by lack of CD11clowB220+Ly6C+CD11b− cells. In parallel, CD11c+ cells isolated from ICSBP KO spleens were unable to produce type I IFNs in response to viral stimulation. ICSBP KO mice also displayed a marked reduction of the DC subset expressing the CD8alpha marker (CD8alpha+ DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP-deficient CD8alpha+ DCs exhibited a markedly impaired phenotype when compared with WT DCs. They expressed very low levels of costimulatory molecules (intercellular adhesion molecule ICAM1, CD40, CD80, CD86) and of the T cell area-homing chemokine receptor CCR7.[4]

Clinical significance

In myeloid cells, IRF8 regulates the expression of Bax and Fas to regulate apoptosis.[5] In chronic myelogenous leukemia (CML), IRF8 regulates acid ceramidase to mediate CML apoptosis.[6]

IRF8 is highly expressed in myeloid cells and was originally identified in as a critical lineage-specific transcription factor for myeloid cell differentiation,[7] recent studies, however, have shown that IRF8 is also constitutively expressed in non-hematopoietic cancer cells, albeit at a lower level. Furthermore, IRF8 can also be up-regulated by IFN-γ in non-hemotopoietic cells. IRF8 mediates the expression of Fas, Bax, FLIP, Jak1 and STAT1 to mediate apoptosis in non-hemotopoietic cancer cells.[8][9][10]

Analysis of human cancer genomics database revealed that IRF8 is not significantly focally amplified across the entire dataset of 3131 tumors, but is significantly focally deleted across the entire dataset of 3131 tumors, suggesting that IRF8 is potentially a tumor suppressor in humans.[11] Molecular analysis indicated that the IRF8 gene promoter is hypermethylated in human colon carcinoma cells,[10][12] suggesting that these cells might use DNA methylation to silence IRF8 expression to advance the disease.

Interactions

IRF8 has been shown to interact with IRF1[13][14] and COPS2.[15]

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: IRF8 interferon regulatory factor 8".
  2. ↑ Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ (December 1992). "Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes". J. Biol. Chem. 267 (35): 25589–96. PMID 1460054.
  3. ↑ Nehyba J, Hrdlicková R, Burnside J, Bose HR (June 2002). "A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein". Mol. Cell. Biol. 22 (11): 3942–57. doi:10.1128/MCB.22.11.3942-3957.2002. PMC 133824. PMID 11997525.
  4. ↑ Tamura T, Ozato K (January 2002). "ICSBP/IRF-8: its regulatory roles in the development of myeloid cells". J. Interferon Cytokine Res. 22 (1): 145–52. doi:10.1089/107999002753452755. PMID 11846985.
  5. ↑ Yang J, Hu X, Zimmerman M, Torres CM, Yang D, Smith SB, Liu K (November 2011). "Cutting edge: IRF8 regulates Bax transcription in vivo in primary myeloid cells". J. Immunol. 187 (9): 4426–30. doi:10.4049/jimmunol.1101034. PMC 3197864. PMID 21949018.
  6. ↑ Hu X, Yang D, Zimmerman M, Liu F, Yang J, Kannan S, Burchert A, Szulc Z, Bielawska A, Ozato K, Bhalla K, Liu K (April 2011). "IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia". Cancer Res. 71 (8): 2882–91. doi:10.1158/0008-5472.CAN-10-2493. PMC 3078194. PMID 21487040.
  7. ↑ Holtschke T, Löhler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring JF, Bachmann MF, Zinkernagel RM, Morse HC, Ozato K, Horak I (October 1996). "Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene". Cell. 87 (2): 307–17. doi:10.1016/S0092-8674(00)81348-3. PMID 8861914.
  8. ↑ Yang D, Wang S, Brooks C, Dong Z, Schoenlein PV, Kumar V, Ouyang X, Xiong H, Lahat G, Hayes-Jordan A, Lazar A, Pollock R, Lev D, Liu K (February 2009). "IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression". Cancer Res. 69 (3): 1080–8. doi:10.1158/0008-5472.CAN-08-2520. PMC 2633427. PMID 19155307.
  9. ↑ Yang D, Thangaraju M, Browning DD, Dong Z, Korchin B, Lev DC, Ganapathy V, Liu K (October 2007). "IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression". J. Immunol. 179 (7): 4775–82. doi:10.4049/jimmunol.179.7.4775. PMID 17878376.
  10. ↑ 10.0 10.1 Yang D, Thangaraju M, Greeneltch K, Browning DD, Schoenlein PV, Tamura T, Ozato K, Ganapathy V, Abrams SI, Liu K (April 2007). "Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells". Cancer Res. 67 (7): 3301–9. doi:10.1158/0008-5472.CAN-06-4068. PMID 17409439.
  11. ↑ "Tumorscape". The Broad Institute.
  12. ↑ McGough JM, Yang D, Huang S, Georgi D, Hewitt SM, Röcken C, Tänzer M, Ebert MP, Liu K (December 2008). "DNA methylation represses IFN-gamma-induced and signal transducer and activator of transcription 1-mediated IFN regulatory factor 8 activation in colon carcinoma cells". Mol. Cancer Res. 6 (12): 1841–51. doi:10.1158/1541-7786.MCR-08-0280. PMC 2605678. PMID 19074829.
  13. ↑ Schaper F, Kirchhoff S, Posern G, Köster M, Oumard A, Sharf R, Levi BZ, Hauser H (October 1998). "Functional domains of interferon regulatory factor I (IRF-1)". Biochem. J. 335 (1): 147–57. PMC 1219763. PMID 9742224.
  14. ↑ Sharf R, Azriel A, Lejbkowicz F, Winograd SS, Ehrlich R, Levi BZ (June 1995). "Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors". J. Biol. Chem. 270 (22): 13063–9. doi:10.1074/jbc.270.22.13063. PMID 7768900.
  15. ↑ Cohen H, Azriel A, Cohen T, Meraro D, Hashmueli S, Bech-Otschir D, Kraft R, Dubiel W, Levi BZ (December 2000). "Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome". J. Biol. Chem. 275 (50): 39081–9. doi:10.1074/jbc.M004900200. PMID 10991940.

Illustrations

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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