IRF8

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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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.[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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