Note | The longer GFI1B variant 1 is the protein refered to in most cases. GFI1B variant 2 shows only a restricted expression in normal cells and could be preferentially associated with leukemic diseases. Functional differences between both proteins are not described yet. |
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| Model for the generation of the two major GFI1B isoforms. GFI1B-V2 is translated from a shorter mRNA splice variant where exon 9 is skipped (aa 171-216 missing). There are many potential 5' transcriptional start sites, but the major start site seems to be in exon 5, corresponding to exon 1 (122 bp) in the RefSeq database. SD: SNAG domain necessary for repression of transcription by GFI1B. ID: Intermediary domain with very low homology to the GFI1B homolog GFI1 and unknown function, which is presumably important for specific protein-protein interactions unique to GFI1B. Znf 1-6: C2H2 zinc-finger domains which are highly conserved between all members of the GFI1 protein family. Znf 3-5 bind to the major groove of target DNA. Znf 4-5 of GFI1B (almost identical to GFI1) recognize a AATC DNA core sequence in the GFI1/GFI1B predicted binding site. |
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Description | GFI1B (isoform 1) is a protein of 330 aa residues and has a predicted molecular mass of 37492.38 Da. Isoelectric point: 9.3076, charge: 25.0, average residue weight: 113613. GFI1B is composed of a 20-amino-acid N-terminal SNAG (SNAIL-GFI) transcription repressor domain, and intermediary domain of largely unknown function and six c-terminal C2H2 zinc-finger domains encompassing residues 163-327. Zinc-fingers 3-5 are involved in sequence specific DNA binding and recognize a taAATCaca/tgca/t core motif. The bases flanking the AATC core motif seem to be poorly conserved. Predictions of true GFI1B binding sites in the genome based only on this sequence have to be validated independently. |
Expression | GFI1B is mainly expressed in the fetal and adult hematopoietic system, where it is detected in hematopoietic stem cells, megakaryocyte/erythroid precursors (MEP), common myeloid precursors (CMP), erythroblasts and early erythrocytes, megakaryocytes and megakaryocyte precursors, B-cell precursors and a small subset of T-cell precursors (Vassen et al., 2007). GFI1B is lso detected in fetal thymus and testes. GFI1B expression varies throughout the maturation of these cells, with the highest expression levels in MEPs, megakaryocytes and erythrocytes and seems to be tightly regulated. The shorter isoform 2 of GFI1B is lowly expressed in normal cells, but upregulated in several types of leukemia (e.g. chronic myelogenous leukemia, acute myeloid leukemia, erythroleukemia, megakaryocytic leukemia). The expression of GFI1B is described to be positively regulated by GATA-1, NF-Y, E2-alpha/TCF3, and HMGB2 and to be repressed by Oct1, GFI1B and GFI1. GFI1B expression is down-regulated by erythropoietin (EPO) in a signal-transducer-and-activator-of-transcription-5 (STAT5) dependent manner. |
Localisation | Almost exclusively nuclear, frequently accumulating in foci of pericentric heterochromatin. |
Function | Negative regulation of transcription. GFI1B is an essential factor in erythroid and megakaryocytic development and differentiation, very likely with proto-oncogenic potential. GFI1B deficiency leads to embryonic lethality in mice due to failure to produce functional erythrocytes and megakaryocytes and increases the apoptosis rate in leukemic cell lines. The GFI1B gene locus can be autoregulated by autorepression of its own promoter in hematopoietic cells (Vassen et al., 2005; Anguita et al., 2010), most likely by interaction with GATA1 (GATA binding protein 1) (Huang et al., 2005), an activator of GFI1B transcription that is also essential for erythroid and megakaryocytic development. GFI1B and its homolog GFI1 show cross-repression, resulting in an enhanced expression of the respective counterpart, when one of these genes is deleted. The repressory activity of GFI1B is achieved by recruiting histone deacetylases (HDAC1 and HDAC2), lysine specific demethylase 1 (LSD1 or KDM1) and the REST corepressor (CoREST) to target DNA sequences (Saleque et al., 2007). GFI1B alters histone methylation at target gene promoters and is associated with sites of gamma-satellite containing heterochromatin (Vassen et al., 2006). GFI1B interacts also with the histone methyltransferases G9a and SUV39H1 and a role in heterochromatin formation is hypothesized (Vassen et al., 2006). GFI1B target genes (e.g. BCL2L1, SOCS1, SOCS3, CDKN1A, GATA3) are frequently also GATA1 target genes (e.g. GFI1B, GATA2, Myb, Myc) and GFI1B is overrepresented at sites where GATA1 binds to repress its target genes (Yu et al., 2009). GATA2 needs to be repressed by GATA1 in developing erythroid cells pointing to an involvement of a GATA1-GFI1B repressory complex in this process. GATA1 and GFI1B have been found in a complex with SUZ12, a member of the polycomb repressory complex 2 (PRC2, SUZ12 and Eed) on repressed genes in MEL (erythroleukemia) cells (Yu et al., 2009). Since GFI1B is also expressed in hematopoietic stem cells (HSC), the existence of such a repressory complex might point to a role of GFI1B in maintaining HSC self renewal, where PCR complexes play a major role. Consistent with this hypothesis, GFI1B can functionally replace GFI1 during hematopoiesis but not in the development of inner ear hair cells, where GFI1 exerts a critical survival function (Fiolka et al., 2006; Wallis et al., 2003). An implication of GFI1B in sensory epithelial cells similar to GFI1 remains to be elucidated. In megakaryocytes GFI1B is found in a complex with GATA1 and ETO2, another corepressor protein that is also implicated in human leukemogenesis (Hamlett et al., 2008), but how GFI1B regulates megakaryocytic development is not clear yet. GFI1B regulates TGF-beta signaling in bipotent erythroid-megakaryocytic progenitors (Randrianarison-Huetz, 2010), which is involved in the control of their differentiation. Finally, GFI1B regulates the expression of GATA3 in T-cell lymphomas, a critical factor for survival of lymphomas and T-cell progenitors (Wei and Kee, 2007). Positive regulation of transcription. GFI1B can activate transcription from a promoter containing four GFI1 consensus-sites in the erythroid cell line K562 (Osawa et al., 2002). |
Homology | GFI1B is highly homologous to its closest relative GFI1. Highly conserved GFI1(B) proteins have been detected in many species from C. elegans to drosophila and human. |
GFI1B controls its own expression binding to multiple sites. |
Anguita E, Villegas A, Iborra F, Hernandez A. |
Haematologica. 2010 Jan;95(1):36-46. Epub 2009 Sep 22. |
PMID 19773260 |
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Growth factor-independent 1B gene (GFI1B) is overexpressed in erythropoietic and megakaryocytic malignancies and increases their proliferation rate. |
Elmaagacli AH, Koldehoff M, Zakrzewski JL, Steckel NK, Ottinger H, Beelen DW. |
Br J Haematol. 2007 Jan;136(2):212-9. Epub 2006 Dec 8. |
PMID 17156408 |
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Gfi1 and Gfi1b act equivalently in haematopoiesis, but have distinct, non-overlapping functions in inner ear development. |
Fiolka K, Hertzano R, Vassen L, Zeng H, Hermesh O, Avraham KB, Duhrsen U, Moroy T. |
EMBO Rep. 2006 Mar;7(3):326-33. Epub 2006 Jan 6. |
PMID 16397623 |
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Gfi-1B plays a critical role in terminal differentiation of normal and transformed erythroid progenitor cells. |
Garcon L, Lacout C, Svinartchouk F, Le Couedic JP, Villeval JL, Vainchenker W, Dumenil D. |
Blood. 2005 Feb 15;105(4):1448-55. Epub 2004 Oct 26. |
PMID 15507521 |
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Characterization of megakaryocyte GATA1-interacting proteins: the corepressor ETO2 and GATA1 interact to regulate terminal megakaryocyte maturation. |
Hamlett I, Draper J, Strouboulis J, Iborra F, Porcher C, Vyas P. |
Blood. 2008 Oct 1;112(7):2738-49. Epub 2008 Jul 14. |
PMID 18625887 |
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Human promoter mutations unveil Oct-1 and GATA-1 opposite action on Gfi1b regulation. |
Hernandez A, Villegas A, Anguita E. |
Ann Hematol. 2010 Aug;89(8):759-65. Epub 2010 Feb 9. |
PMID 20143233 |
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GATA-1 mediates auto-regulation of Gfi-1B transcription in K562 cells. |
Huang DY, Kuo YY, Chang ZF. |
Nucleic Acids Res. 2005 Sep 21;33(16):5331-42. Print 2005. |
PMID 16177182 |
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Regulation of Socs gene expression by the proto-oncoprotein GFI-1B: two routes for STAT5 target gene induction by erythropoietin. |
Jegalian AG, Wu H. |
J Biol Chem. 2002 Jan 18;277(3):2345-52. Epub 2001 Nov 5. |
PMID 11696536 |
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Gene profiling of growth factor independence 1B gene (Gfi-1B) in leukemic cells. |
Koldehoff M, Zakrzewski JL, Klein-Hitpass L, Beelen DW, Elmaagacli AH. |
Int J Hematol. 2008 Jan;87(1):39-47. Epub 2007 Dec 6. |
PMID 18224412 |
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GATA-1 and Gfi-1B interplay to regulate Bcl-xL transcription. |
Kuo YY, Chang ZF. |
Mol Cell Biol. 2007 Jun;27(12):4261-72. Epub 2007 Apr 9. |
PMID 17420275 |
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High-mobility group protein HMGB2 regulates human erythroid differentiation through trans-activation of GFI1B transcription. |
Laurent B, Randrianarison-Huetz V, Marchal V, Mayeux P, Dusanter-Fourt I, Dumenil D. |
Blood. 2010 Jan 21;115(3):687-95. Epub 2009 Nov 24. |
PMID 19965638 |
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Erythroid expansion mediated by the Gfi-1B zinc finger protein: role in normal hematopoiesis. |
Osawa M, Yamaguchi T, Nakamura Y, Kaneko S, Onodera M, Sawada K, Jegalian A, Wu H, Nakauchi H, Iwama A. |
Blood. 2002 Oct 15;100(8):2769-77. |
PMID 12351384 |
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Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia. |
Qian Z, Joslin JM, Tennant TR, Reshmi SC, Young DJ, Stoddart A, Larson RA, Le Beau MM. |
Chem Biol Interact. 2010 Mar 19;184(1-2):50-7. Epub 2009 Dec 1. (REVIEW) |
PMID 19958752 |
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Gfi-1B controls human erythroid and megakaryocytic differentiation by regulating TGF-beta signaling at the bipotent erythro-megakaryocytic progenitor stage. |
Randrianarison-Huetz V, Laurent B, Bardet V, Blobe GC, Huetz F, Dumenil D. |
Blood. 2010 Apr 8;115(14):2784-95. Epub 2010 Feb 2. |
PMID 20124515 |
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The human homologue (GFI1B) of the chicken GFI gene maps to chromosome 9q34.13-A locus frequently altered in hematopoietic diseases. |
Rodel B, Wagner T, Zornig M, Niessing J, Moroy T. |
Genomics. 1998 Dec 15;54(3):580-2. |
PMID 9878267 |
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GATA-1 forms distinct activating and repressive complexes in erythroid cells. |
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EMBO J. 2005 Jul 6;24(13):2354-66. Epub 2005 May 26. |
PMID 15920471 |
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Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. |
Saleque S, Kim J, Rooke HM, Orkin SH. |
Mol Cell. 2007 Aug 17;27(4):562-72. |
PMID 17707228 |
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The Gfi-1B proto-oncoprotein represses p21WAF1 and inhibits myeloid cell differentiation. |
Tong B, Grimes HL, Yang TY, Bear SE, Qin Z, Du K, El-Deiry WS, Tsichlis PN. |
Mol Cell Biol. 1998 May;18(5):2462-73. |
PMID 9566867 |
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Erythropoiesis: model systems, molecular regulators, and developmental programs. |
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IUBMB Life. 2009 Aug;61(8):800-30. (REVIEW) |
PMID 19621348 |
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Gfi1b alters histone methylation at target gene promoters and sites of gamma-satellite containing heterochromatin. |
Vassen L, Fiolka K, Moroy T. |
EMBO J. 2006 Jun 7;25(11):2409-19. Epub 2006 May 11. |
PMID 16688220 |
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Growth factor independent 1b (Gfi1b) and a new splice variant of Gfi1b are highly expressed in patients with acute and chronic leukemia. |
Vassen L, Khandanpour C, Ebeling P, van der Reijden BA, Jansen JH, Mahlmann S, Duhrsen U, Moroy T. |
Int J Hematol. 2009 May;89(4):422-30. Epub 2009 Apr 10. |
PMID 19360458 |
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Gfi1b:green fluorescent protein knock-in mice reveal a dynamic expression pattern of Gfi1b during hematopoiesis that is largely complementary to Gfi1. |
Vassen L, Okayama T, Moroy T. |
Blood. 2007 Mar 15;109(6):2356-64. Epub 2006 Nov 9. |
PMID 17095621 |
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The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival. |
Wallis D, Hamblen M, Zhou Y, Venken KJ, Schumacher A, Grimes HL, Zoghbi HY, Orkin SH, Bellen HJ. |
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PMID 12441305 |
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Oncogene. 2007 Oct 15;26(47):6803-15. (REVIEW) |
PMID 17934487 |
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Growth factor independent 1B (Gfi1b) is an E2A target gene that modulates Gata3 in T-cell lymphomas. |
Xu W, Kee BL. |
Blood. 2007 May 15;109(10):4406-14. Epub 2007 Feb 1. |
PMID 17272506 |
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Mol Cell. 2009 Nov 25;36(4):682-95. |
PMID 19941827 |
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Inferring the functional effects of mutation through clusters of mutations in homologous proteins. |
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Hum Mutat. 2010 Mar;31(3):264-71. |
PMID 20052764 |
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