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zinc finger protein Gfi-1; growth factor independent protein 1; zinc finger protein 163 (GFI1, ZNF163)
Function:
- transcription repressor essential for hematopoiesis
- functions in a cell-context & development-specific manner
- binds to 5'-TAAATCAC[AT]GCA-3' in the promoter region of a large number of genes
- component of several complexes, including
- EHMT2-GFI1-HDAC1
- AJUBA-GFI1-HDAC1
- RCOR-GFI-KDM1A-HDAC
- these complexes suppress, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development
- regulates neutrophil differentiation, promotes proliferation of lymphoid cells, & is required for granulocyte development
- mediates, together with U2AF1L4, the alternative splicing of CD45 & controls T-cell receptor signaling
- regulates the endotoxin- mediated Toll-like receptor inflammatory response by antagonizing RELA
- cooperates with CBFA2T2 to regulate ITGB1-dependent neurite growth
- controls cell-cycle progression by repressing CDKNIA/p21 transcription in response to TGFB1 via recruitment of GFI1 by ZBTB17 to the CDKNIA/p21 promoter
- required for maintenance of inner ear hair cells
- ubiquitinated
- ubiquitination & degradation by the proteasome is inhibited by the ubiquitin ligase, ARIH2
- interacts with U2AF1L4
- component of RCOR-GFI-KDM1A-HDAC complexes
- interacts directly with RCOR1, KDM1A & HDAC2
- also interacts with HDAC1
- interacts (via the Zn+2-finger domain) with ARIH2
- the interaction prevents GFI1 ubiquitination & proteasomal degradation
- interacts with PIAS3
- the interaction relieves the inhibitory effect of PIAS3 on STAT3-mediated transcriptional activity
- forms a complex with EHMT2 & HDAC1 to promote Lys-9 dimethylation of H3 (H3K9Me2) & repress expression of target genes
- interacts directly with EHMT2
- component of the GFI1-AJUBA-HDAC1 repressor complex
- interacts directly with AJUBA (via ITS LIM domains);
- the interaction results in the HDAC-dependent corepression of a subset of GFI1 target genes &, occurs independently of the SNAG domain
- interacts with SPI1
- the interaction inhibits SPI1 transcriptional activity & represses SPI1-regulated macrophage-specific genes required for proper granulocyte development
- interacts with RUNX1T1;
- the interaction represses HDAC-mediated transcriptional activity
- interacts with RELA; the interaction occurs on liposaccharide (LPS) stimulation & controls RELA DNA binding activity & regulates endotoxin-mediated TOLL-like receptor inflammatory response
- interacts (via the C-terminal Zn+2 fingers) with ZBTB17
- the interaction results in the recruitment of GFI1 to the CDKN1A/p21 promoter & repression of CDKN1A/p21 transcription
Structure:
- C2H2-type Zn+2 fingers 3, 4 & 5 are required for DNA-binding & for interaction with SPI1
- the SNAG domain of GFIs is required for nuclear location & for interaction with some corepressors (putative)
- contains 6 C2H2-type Zn+2 fingers
Compartment:
- nucleus
- colocalizes with PIAS3 & RUNX1T1 in nuclear dots
Expression: down-regulated by TGFB1
Pathology:
- defects in GFI1 are a cause of
a) neutropenia severe congenital autosomal dominant type 2 b)dominant nonimmune chronic idiopathic neutropenia of adults
General
C2H2 type zinc finger protein
phosphoprotein
transcriptional silencer (transcriptional repressor)
Properties
SIZE: entity length = 422 aa
MW = 45 kD
COMPARTMENT: cell nucleus
MOTIF: SNAG domain {1-20}
Ser phosphorylation site {S56}
RELA interaction {140-257}
MOTIF: glycine-rich region {158-209}
Zn finger C2H2-type
SITE: 255-278
EFFECTOR-BOUND: Zn+2
Zn finger C2H2-type
SITE: 284-306
EFFECTOR-BOUND: Zn+2
Zn finger C2H2-type
SITE: 312-334
EFFECTOR-BOUND: Zn+2
Zn finger C2H2-type
SITE: 340-362
EFFECTOR-BOUND: Zn+2
Zn finger C2H2-type
SITE: 368-390
EFFECTOR-BOUND: Zn+2
Zn finger C2H2-type
SITE: 396-419
EFFECTOR-BOUND: Zn+2
Database Correlations
OMIM correlations
MORBIDMAP 600871
UniProt Q99684
Pfam PF00096
Entrez Gene 2672
Kegg hsa:2672
References
- UniProt :accession Q99684
- GFI1base; Note: GFI1 mutation db
http://bioinf.uta.fi/GFI1base/