Q99684 (GFI1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Zinc finger protein Gfi-1

Alternative name(s):
Growth factor independent protein 1
Zinc finger protein 163

Gene names

Name:	GFI1
Synonyms:	ZNF163

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	422 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Transcription repressor essential for hematopoiesis. Functions in a cell-context and 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 the EHMT2-GFI1-HDAC1, AJUBA-GFI1-HDAC1 and RCOR-GFI-KDM1A-HDAC complexes, that suppress, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Regulates neutrophil differentiation, promotes proliferation of lymphoid cells, and is required for granulocyte development. Mediates, together with U2AF1L4, the alternative splicing of CD45 and controls T-cell receptor signaling. Regulates the endotoxin-mediated Toll-like receptor (TLR) 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 and CDKNIB promoters. Required for the maintenance of inner ear hair cells. Ref.3 Ref.4 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14
Subunit structure	Interacts with U2AF1L4. Component of RCOR-GFI-KDM1A-HDAC complexes. Interacts directly with RCOR1, KDM1A and HDAC2 By similarity. Also interacts with HDAC1. Interacts (via the zinc-finger domain) with ARIH2; the interaction prevents GFI1 ubiquitination and proteasomal degradation. Interacts with PIAS3; the interaction relieves the inhibitory effect of PIAS3 on STAT3-mediated transcriptional activity. Forms a complex with EHMT2 and HDAC1 to promote 'Lys-9' dimethylation of H3 (H3K9Me2) and 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 and, occurs independently of the SNAG domain. Interacts with SPI1; the interaction inhibits SPI1 transcriptional activity and 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 and controls RELA DNA binding activity and regulates endotoxin-mediated TOLL-like receptor inflammatory response. Interacts (via the C-terminal zinc fingers) with ZBTB17; the interaction results in the recruitment of GFI1 to the CDKN1A/p21 and CDKN1B promoters and repression of transcription. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.13
Subcellular location	Nucleus. Note: Colocalizes with PIAS3 and RUNX1T1 in nuclear dots. Ref.3 Ref.4 Ref.5 Ref.9 Ref.12
Induction	Down-regulated by TGFB1. Ref.12 Ref.13
Domain	Zinc fingers 3, 4 and 5 are required for DNA-binding and for interaction with SPI1. Ref.8 The SNAG domain of GFIs is required for nuclear location and for interaction with some corepressors By similarity. Ref.8
Post-translational modification	Ubiquitinated. Ubiquitination and degradation by the proteasome is inhibited by the ubiquitin ligase, ARIH2. Ref.7
Involvement in disease	Neutropenia severe congenital autosomal dominant 2 (SCN2) [MIM:613107]: A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14 Dominant nonimmune chronic idiopathic neutropenia of adults (NI-CINA) [MIM:607847]: Relatively mild form of neutropenia diagnosed in adults, but predisposing to leukemia in a subset of patients. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14
Sequence similarities	Contains 6 C2H2-type zinc fingers.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Repeat Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
PTM	Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	auditory receptor cell differentiation Inferred from electronic annotation. Source: Compara cell fate commitment Inferred from electronic annotation. Source: Compara cellular response to lipopolysaccharide Inferred from expression pattern Ref.12. Source: UniProtKB inner ear morphogenesis Inferred from electronic annotation. Source: Compara mechanosensory behavior Inferred from electronic annotation. Source: Compara negative regulation of NF-kappaB transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of calcidiol 1-monooxygenase activity Inferred from direct assay PubMed 15947108. Source: BHF-UCL negative regulation of cell fate specification Inferred from electronic annotation. Source: Compara negative regulation of neuron projection development Inferred from direct assay Ref.10. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 15947108. Source: BHF-UCL negative regulation of vitamin D biosynthetic process Inferred by curator PubMed 15947108. Source: BHF-UCL positive regulation of cell fate specification Inferred from electronic annotation. Source: Compara positive regulation of interleukin-6-mediated signaling pathway Inferred from direct assay Ref.4. Source: UniProtKB regulation of toll-like receptor signaling pathway Inferred from direct assay Ref.12. Source: UniProtKB regulation of transcription involved in G1/S phase of mitotic cell cycle Traceable author statement PubMed 8441411. Source: ProtInc transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW viral reproduction Traceable author statement PubMed 8441411. Source: ProtInc
Cellular_component	nuclear body Inferred from direct assay Ref.4. Source: UniProtKB nuclear matrix Inferred from direct assay Ref.5. Source: UniProtKB transcriptional repressor complex Inferred from direct assay Ref.5. Source: UniProtKB
Molecular_function	transcription regulatory region DNA binding Inferred from direct assay PubMed 15947108. Source: BHF-UCL zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Ajuba	Q91XC0	4	EBI-949368,EBI-1565930	From a different organism.
CHAF1A	Q13111	4	EBI-949368,EBI-1020839
EHMT2	Q96KQ7	2	EBI-949368,EBI-744366
HDAC1	Q13547	4	EBI-949368,EBI-301834
PRDM5	Q9NQX1	2	EBI-949368,EBI-4292031
RELA	Q04206	2	EBI-949368,EBI-73886
Spi1	P17433	2	EBI-949368,EBI-607588	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 422	422	Zinc finger protein Gfi-1		PRO_0000047193
Regions
	Zinc finger	255 – 278	24	C2H2-type 1
	Zinc finger	284 – 306	23	C2H2-type 2
	Zinc finger	312 – 334	23	C2H2-type 3
	Zinc finger	340 – 362	23	C2H2-type 4
	Zinc finger	368 – 390	23	C2H2-type 5
	Zinc finger	396 – 419	24	C2H2-type 6
	Region	1 – 20	20	SNAG domain By similarity
	Region	140 – 257	118	Required for interaction with RELA
	Compositional bias	158 – 209	52	Ala/Gly-rich
Natural variations
	Natural variant	36	1	S → N. Corresponds to variant rs34631763 [ dbSNP | Ensembl ].		VAR_052722
	Natural variant	382	1	N → S in SCN2; zero neutrophil count. marked monocytosis and reduced T- and B-lymphocyte number leading to recurrent infectious complications. Abolishes recognition of DNA binding site of zinc finger. Diminished repression activity and elevated ELA2 expression. No effect on repression of CDKN1A/p21 transcription. Ref.13 Ref.14 Corresponds to variant rs28936381 [ dbSNP | Ensembl ].		VAR_016212
	Natural variant	403	1	K → R in NI-CINA; Neutropenic and elevated monocytosis but no history of infectious complications. No effect on DNA binding but diminished GFI1 repression activity. Ref.14 Corresponds to variant rs28936382 [ dbSNP | Ensembl ].		VAR_016213
Experimental info
	Mutagenesis	2	1	P → A: Abrogates transcriptional repression. Ref.8
	Sequence conflict	73 – 77	5	DSCEG → RQLRS in AAB37272. Ref.1
	Sequence conflict	184 – 186	3	SCS → NCI in AAB37272. Ref.1
	Sequence conflict	213	1	R → K in AAB37272. Ref.1
	Sequence conflict	228	1	G → R in AAB37272. Ref.1
	Sequence conflict	232	1	D → N in AAB37272. Ref.1
	Sequence conflict	367	1	P → L in AAB37272. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q99684 [UniParc]. Last modified August 15, 2003. Version 2. Checksum: 740A466F72C5FC72	FASTA	422	45,297
	10 20 30 40 50 60 MPRSFLVKSK KAHSYHQPRS PGPDYSLRLE NVPAPSRADS TSNAGGAKAE PRDRLSPESQ 70 80 90 100 110 120 LTEAPDRASA SPDSCEGSVC ERSSEFEDFW RPPSPSASPA SEKSMCPSLD EAQPFPLPFK 130 140 150 160 170 180 PYSWSGLAGS DLRHLVQSYR PCGALERGAG LGLFCEPAPE PGHPAALYGP KRAAGGAGAG 190 200 210 220 230 240 APGSCSAGAG ATAGPGLGLY GDFGSAAAGL YERPTAAAGL LYPERGHGLH ADKGAGVKVE 250 260 270 280 290 300 SELLCTRLLL GGGSYKCIKC SKVFSTPHGL EVHVRRSHSG TRPFACEMCG KTFGHAVSLE 310 320 330 340 350 360 QHKAVHSQER SFDCKICGKS FKRSSTLSTH LLIHSDTRPY PCQYCGKRFH QKSDMKKHTF 370 380 390 400 410 420 IHTGEKPHKC QVCGKAFSQS SNLITHSRKH TGFKPFGCDL CGKGFQRKVD LRRHRETQHG LK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning of the human Gfi-1 gene and its mapping to chromosome region 1p22." Roberts T., Cowell J.K. Oncogene 14:1003-1005(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Bone marrow.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung and Testis.
[3]	"Gfi-1 encodes a nuclear zinc finger protein that binds DNA and functions as a transcriptional repressor." Zweidler-Mckay P.A., Grimes H.L., Flubacher M.M., Tsichlis P.N. Mol. Cell. Biol. 16:4024-4034(1996) [PubMed] [Europe PMC] [Abstract] Cited for: DNA-BINDING, SUBCELLULAR LOCATION, FUNCTION.
[4]	"The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3." Roedel B., Tavassoli K., Karsunky H., Schmidt T., Bachmann M., Schaper F., Heinrich P., Shuai K., Elsaesser H.-P., Moeroey T. EMBO J. 19:5845-5855(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PIAS3, SUBCELLULAR LOCATION, FUNCTION.
[5]	"Gfi-1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA-sensitive mechanism." McGhee L., Bryan J., Elliott L., Grimes H.L., Kazanjian A., Davis J.N., Meyers S. J. Cell. Biochem. 89:1005-1018(2003) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH RUNX1T1; HDAC1; HDAC2 AND HDAC3, INTERACTION WITH RUNX1T1, SUBCELLULAR LOCATION.
[6]	"Gfi1 coordinates epigenetic repression of p21Cip/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1." Duan Z., Zarebski A., Montoya-Durango D., Grimes H.L., Horwitz M. Mol. Cell. Biol. 25:10338-10351(2005) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH EHMT2 AND HDAC1, INTERACTION WITH EHMT2 AND HDAC1, FUNCTION.
[7]	"Gfi1 ubiquitination and proteasomal degradation is inhibited by the ubiquitin ligase Triad1." Marteijn J.A., van der Meer L.T., van Emst L., van Reijmersdal S., Wissink W., de Witte T., Jansen J.H., Van der Reijden B.A. Blood 110:3128-3135(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH ARIH2, UBIQUITINATION.
[8]	"The transcriptional repressor GFI-1 antagonizes PU.1 activity through protein-protein interaction." Dahl R., Iyer S.R., Owens K.S., Cuylear D.D., Simon M.C. J. Biol. Chem. 282:6473-6483(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SPI1, DOMAIN ZINC FINGER, FUNCTION, MUTAGENESIS OF PRO-2.
[9]	"Ajuba functions as a histone deacetylase-dependent co-repressor for autoregulation of the growth factor-independent-1 transcription factor." Montoya-Durango D.E., Velu C.S., Kazanjian A., Rojas M.E., Jay C.M., Longmore G.D., Grimes H.L. J. Biol. Chem. 283:32056-32065(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH AJUBA IN THE GFI1-AJUBA-HDAC COMPLEX, SUBCELLULAR LOCATION, FUNCTION.
[10]	"Loss of function genetic screens reveal MTGR1 as an intracellular repressor of beta1 integrin-dependent neurite outgrowth." Ossovskaya V.S., Dolganov G., Basbaum A.I. J. Neurosci. Methods 177:322-333(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"Gfi-1 represses CDKN2B encoding p15INK4B through interaction with Miz-1." Basu S., Liu Q., Qiu Y., Dong F. Proc. Natl. Acad. Sci. U.S.A. 106:1433-1438(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH ZBTB17.
[12]	"Zinc finger protein Gfi1 controls the endotoxin-mediated Toll-like receptor inflammatory response by antagonizing NF-kappaB p65." Sharif-Askari E., Vassen L., Kosan C., Khandanpour C., Gaudreau M.C., Heyd F., Okayama T., Jin J., Rojas M.E., Grimes H.L., Zeng H., Moroy T. Mol. Cell. Biol. 30:3929-3942(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH RELA, SUBCELLULAR LOCATION, INDUCTION, FUNCTION.
[13]	"A role of Miz-1 in Gfi-1-mediated transcriptional repression of CDKN1A." Liu Q., Basu S., Qiu Y., Tang F., Dong F. Oncogene 29:2843-2852(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ZBTB17, FUNCTION, INDUCTION, CHARACTERIZATION OF VARIANT SER-382.
[14]	"Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2." Person R.E., Li F.-Q., Duan Z., Benson K.F., Wechsler J., Papadaki H.A., Eliopoulos G., Kaufman C., Bertolone S.J., Nakamoto B., Papayannopoulou T., Grimes H.L., Horwitz M. Nat. Genet. 34:308-312(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT NI-CINA ARG-403, VARIANT SCN2 SER-382, CHARACTERIZATION OF VARIANTS NI-CINA ARG-403 AND SCN2 SER-382, FUNCTION.
+	Additional computationally mapped references.

Web resources

GFI1base

GFI1 mutation db

Cross-references

Sequence databases
EMBL GenBank DDBJ	U67369 mRNA. Translation: AAB37272.1. BC032751 mRNA. Translation: AAH32751.1. BC074866 mRNA. Translation: AAH74866.1. BC074867 mRNA. Translation: AAH74867.1.
IPI	IPI00017068.
RefSeq	NP_001120687.1. NM_001127215.1. NP_001120688.1. NM_001127216.1. NP_005254.2. NM_005263.3.
UniGene	Hs.73172.
3D structure databases
ProteinModelPortal	Q99684.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-38452N.
IntAct	Q99684. 14 interactions.
MINT	MINT-149356.
STRING	9606.ENSP00000294702.
PTM databases
PhosphoSite	Q99684.
Polymorphism databases
DMDM	33860154.
Proteomic databases
PaxDb	Q99684.
PRIDE	Q99684.
Protocols and materials databases
DNASU	2672.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000294702; ENSP00000294702; ENSG00000162676. ENST00000370332; ENSP00000359357; ENSG00000162676. ENST00000427103; ENSP00000399719; ENSG00000162676.
GeneID	2672.
KEGG	hsa:2672.
UCSC	uc001dou.4. human.
Organism-specific databases
CTD	2672.
GeneCards	GC01M092940.
HGNC	HGNC:4237. GFI1.
HPA	CAB011197.
MIM	600871. gene. 607847. phenotype. 613107. phenotype.
neXtProt	NX_Q99684.
Orphanet	486. Autosomal dominant severe congenital neutropenia.
PharmGKB	PA24344.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG5048.
HOVERGEN	HBG006967.
InParanoid	Q99684.
KO	K09223.
OMA	APEPGHP.
OrthoDB	EOG48PMK8.
PhylomeDB	Q99684.
Gene expression databases
ArrayExpress	Q99684.
Bgee	Q99684.
CleanEx	HS_GFI1.
Genevestigator	Q99684.
GermOnline	ENSG00000162676. Homo sapiens.
Family and domain databases
Gene3D	3.30.160.60. 6 hits.
InterPro	IPR007087. Znf_C2H2. IPR015880. Znf_C2H2-like. IPR013087. Znf_C2H2/integrase_DNA-bd. IPR001878. Znf_CCHC. [Graphical view]
Pfam	PF00096. zf-C2H2. 1 hit. [Graphical view]
SMART	SM00355. ZnF_C2H2. 6 hits. SM00343. ZnF_C2HC. 1 hit. [Graphical view]
PROSITE	PS00028. ZINC_FINGER_C2H2_1. 6 hits. PS50157. ZINC_FINGER_C2H2_2. 6 hits. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	2672.
NextBio	10546.
SOURCE	Search...

Entry information

Entry name

GFI1_HUMAN

Accession

Primary (citable) accession number: Q99684
Secondary accession number(s): Q8N564

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	August 15, 2003
Last modified:	May 1, 2013
This is version 122 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.