Q9R1Y5 (HIC1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Hypermethylated in cancer 1 protein
Short name=Hic-1

Gene names

Name:

Hic1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	733 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Transcriptional repressor. Recognizes and binds to the consensus sequence '5-[CG]NG[CG]GGGCA[CA]CC-3'. May act as a tumor suppressor. May be involved in development of head, face, limbs and ventral body wall. Involved in down-regulation of SIRT1 and thereby is involved in regulation of p53/TP53-dependent apoptotic DNA-damage responses. The specific target gene promoter association seems to be depend on corepressors, such as CTBP1 or CTBP2 and MTA1. The regulation of SIRT1 transcription in response to nutrient deprivation seems to involve CTBP1. In cooperation with MTA1 (indicative for an association with the NuRD complex) represses transcription from CCND1/cyclin-D1 and CDKN1C/p57Kip2 specifically in quiescent cells. Involved in regulation of the Wnt signaling pathway probably by association with TCF7L2 and preventing TCF7L2 and CTNNB1 association with promoters of TCF-responsive genes. Seems to repress transcription from E2F1 and ATOH1 which involves ARID1A, indicative for the participation of a distinct SWI/SNF-type chromatin-remodeling complex. Probably represses transcription from CXCR7, FGFBP1 and EFNA1. Ref.7 Ref.9
Subunit structure	Self-associates. Interacts with HIC2. Interacts with CTBP1 and CTBP2. Interacts with TCF7L2 and ARID1A. Interacts with MTA1 and MBD3; indicative for an association with the NuRD complex By similarity. Ref.7
Subcellular location	Nucleus Probable.
Tissue specificity	Ubiquitously expressed with highest levels in heart and lung. Ref.2
Developmental stage	Expression is first detected in the embryo after 9 dpc. In the embryo, expression is found in restricted regions of somite derivatives, limb anlagen and cranio-facial mesenchyme. In the fetus, it is additionally expressed in mesenchymes apposed to precartilaginous condensations, at many interfaces to budding epithelia of inner organs, and weakly in muscles. Ref.1
Domain	The BTB domain inhibits the binding to a single consensus binding site, but mediates cooperative binding to multiple binding sites By similarity.
Post-translational modification	Acetylated on several residues, including Lys-333. Lys-333 is deacetylated by SIRT1 By similarity. Sumoylated on Lys-333 by a PIAS family member, which enhances interaction with MTA1, positively regulates transcriptional repression activity and is enhanced by HDAC4 By similarity.
Involvement in disease	Defects in Hic1 are the cause of perinatal death with serious developmental anomalies, including acrania, exencephaly, cleft palate, omphalocele, craniofacial and limb anomalies. Ref.2
Disruption phenotype	Impaired development resulting in embryonic and perinatal lethality. Mice disrupted in the germ line for only one allele of Hic1 develop many different spontaneous malignant tumors, including a predominance of epithelial cancers in males and lymphomas and sarcomas in females. The complete loss of Hic1 function in the heterozygous mice seems to involve dense methylation of the promoter of the remaining wild-type allele. Ref.6
Sequence similarities	Belongs to the krueppel C2H2-type zinc-finger protein family. Hic subfamily. Contains 1 BTB (POZ) domain. Contains 5 C2H2-type zinc fingers.
Sequence caution	The sequence AAD30654.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened. The sequence AAD30655.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Biological process	Transcription Transcription regulation Wnt signaling pathway
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Developmental protein Repressor
PTM	Acetylation Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW intrinsic apoptotic signaling pathway in response to DNA damage Inferred from direct assay Ref.7. Source: UniProtKB multicellular organismal development Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of Wnt receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay Ref.7. Source: UniProtKB positive regulation of DNA damage response, signal transduction by p53 class mediator Inferred from mutant phenotype Ref.7. Source: UniProtKB transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	chromatin Inferred from direct assay Ref.7. Source: UniProtKB cytoplasm Inferred from electronic annotation. Source: Compara nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	histone deacetylase binding Inferred from sequence or structural similarity. Source: UniProtKB sequence-specific DNA binding Inferred from sequence or structural similarity. Source: UniProtKB sequence-specific DNA binding transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Sirt1	Q923E4	2	EBI-5236187,EBI-1802585

Alternative products

This entry describes 1 isoform produced by alternative splicing. [Select]

Note: A number of isoforms may be produced.

Isoform 1 (identifier: Q9R1Y5-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 733	733	Hypermethylated in cancer 1 protein		PRO_0000046943
Regions
	Domain	47 – 110	64	BTB
	Zinc finger	437 – 464	28	C2H2-type 1
	Zinc finger	507 – 534	28	C2H2-type 2
	Zinc finger	535 – 562	28	C2H2-type 3
	Zinc finger	563 – 590	28	C2H2-type 4
	Zinc finger	591 – 618	28	C2H2-type 5
	Region	154 – 315	162	Mediates HDAC-dependent transcriptional repression By similarity
	Region	241 – 247	7	Interaction with CTBP1 By similarity
	Compositional bias	1 – 13	13	Arg/Gly/Pro-rich
	Compositional bias	112 – 119	8	Poly-Ala
	Compositional bias	160 – 167	8	Poly-Gly
	Compositional bias	195 – 199	5	Poly-Pro
Amino acid modifications
	Modified residue	313	1	Phosphoserine Ref.8
	Modified residue	333	1	N6-acetyllysine; alternate By similarity
	Cross-link	333		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate By similarity
Experimental info
	Sequence conflict	19	1	T → M in AAD30654. Ref.1
	Sequence conflict	19	1	T → M in AAD30655. Ref.1
	Sequence conflict	19	1	T → M no nucleotide entry Ref.4
	Sequence conflict	83	1	N → S in AAD30654. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 14, 2011. Version 4. Checksum: 912C253ED2C25E61	FASTA	733	76,828
	10 20 30 40 50 60 MTFPEADILL KSGECAGQTM LDTMEAPGHS RQLLLQLNNQ RTKGFLCDVI IVVQNALFRA 70 80 90 100 110 120 HKNVLAASSA YLKSLVVHDN LLNLDHDMVS PAVFRLVLDF IYTGRLTDSV EAAAAAAVAP 130 140 150 160 170 180 GAEPSLGAVL AAASYLQIPD LVALCKKRLK RHGKYCHLRG GGSGGGGYAP YGRPGRGLRA 190 200 210 220 230 240 ATPVIQACYS SPAGPPPPPA AEPPSGPDAA VNTHCAELYA SGPGPAASLC APERRCSPLC 250 260 270 280 290 300 GLDLSKKSPP GSSVPERPLS ERELPPRPDS PPGAGPAVYK EPSLALPPLP PLPFQKLEEA 310 320 330 340 350 360 VPTPDPFRGS GGSPGPEPPG RPDGSSLLYR WMKHEPGLGS YGDELVRDRG SPGERLEERG 370 380 390 400 410 420 GDPAASPGGP PLGLVPPPRY PGSLDGPGTG ADGDDYKSSS EETGSSEDPS PPGGHLEGYP 430 440 450 460 470 480 CPHLAYGEPE SFGDNLYVCI PCGKGFPSSE QLNAHVEAHV EEEEALYGRA EAAEVAAGAA 490 500 510 520 530 540 GLGPPFGGGG DKVTGAPGGL GELLRPYRCA SCDKSYKDPA TLRQHEKTHW LTRPYPCTIC 550 560 570 580 590 600 GKKFTQRGTM TRHMRSHLGL KPFACDACGM RFTRQYRLTE HMRIHSGEKP YECQVCGGKF 610 620 630 640 650 660 AQQRNLISHM KMHAVGGAAG AAGALAGLGG LPGVPGPDGK GKLDFPEGVF AVARLTAEQL 670 680 690 700 710 720 SLKQQDKAAA AELLAQTTHF LHDPKVALES LYPLAKFTAE LGLSPDKAAE VLSQGAHLAA 730 GPDSRTIDRF SPT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome." Grimm C., Spoerle R., Schmid T.E., Adler I.-D., Adamski J., Schughart K., Graw J. Hum. Mol. Genet. 8:697-710(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], NUCLEOTIDE SEQUENCE [MRNA] OF 13-733, DEVELOPMENTAL STAGE. Strain: 129/Sv and Swiss Webster. Tissue: Embryo.
[2]	"Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome." Carter M.G., Johns M.A., Zeng X., Zhou L., Zink M.C., Mankowski J.L., Donovan D.M., Baylin S.B. Hum. Mol. Genet. 9:413-419(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE, DISEASE, TISSUE SPECIFICITY.
[3]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[4]	"Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53." Guerardel C., Deltour S., Pinte S., Monte D., Begue A., Godwin A.K., Leprince D. J. Biol. Chem. 276:3078-3089(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-20, PROMOTER USAGE.
[5]	"Evolutionary divergence in the broad complex, tramtrack and bric a brac/poxviruses and zinc finger domain from the candidate tumor suppressor gene hypermethylated in cancer." Guerardel C., Deltour S., Leprince D. FEBS Lett. 451:253-256(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 20-179. Strain: 129/Sv. Tissue: Liver.
[6]	"Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors." Chen W.Y., Zeng X., Carter M.G., Morrell C.N., Chiu Yen R.W., Esteller M., Watkins D.N., Herman J.G., Mankowski J.L., Baylin S.B. Nat. Genet. 33:197-202(2003) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[7]	"Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses." Chen W.Y., Wang D.H., Yen R.C., Luo J., Gu W., Baylin S.B. Cell 123:437-448(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH SIRT1.
[8]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-313, MASS SPECTROMETRY. Tissue: Liver.
[9]	"Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma." Briggs K.J., Corcoran-Schwartz I.M., Zhang W., Harcke T., Devereux W.L., Baylin S.B., Eberhart C.G., Watkins D.N. Genes Dev. 22:770-785(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[10]	Erratum Briggs K.J., Corcoran-Schwartz I.M., Zhang W., Harcke T., Devereux W.L., Baylin S.B., Eberhart C.G., Watkins D.N. Genes Dev. 22:1410-1410(2008)
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF036334 mRNA. Translation: AAD30654.1. Different initiation. AF036582 Genomic DNA. Translation: AAD30655.1. Sequence problems. AL603905 Genomic DNA. Translation: CAI35087.1. AJ132691 Genomic DNA. Translation: CAB44493.1.
IPI	IPI00129231.
RefSeq	NP_001091673.1. NM_001098203.1.
UniGene	Mm.57250.
3D structure databases
ProteinModelPortal	Q9R1Y5.
SMR	Q9R1Y5. Positions 25-145, 429-613.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9R1Y5. 2 interactions.
MINT	MINT-2731109.
PTM databases
PhosphoSite	Q9R1Y5.
Proteomic databases
PaxDb	Q9R1Y5.
PRIDE	Q9R1Y5.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	15248.
KEGG	mmu:15248.
UCSC	uc007kdc.1. mouse.
Organism-specific databases
CTD	3090.
MGI	MGI:1338010. Hic1.
Phylogenomic databases
eggNOG	COG5048.
GeneTree	ENSGT00700000104525.
HOGENOM	HOG000026793.
HOVERGEN	HBG031606.
InParanoid	B1ARH0.
OrthoDB	EOG4RV2TP.
Gene expression databases
ArrayExpress	Q9R1Y5.
Bgee	Q9R1Y5.
CleanEx	MM_HIC1.
Genevestigator	Q9R1Y5.
GermOnline	ENSMUSG00000043099. Mus musculus.
Family and domain databases
Gene3D	3.30.160.60. 4 hits. 3.30.710.10. 1 hit.
InterPro	IPR000210. BTB/POZ-like. IPR011333. BTB/POZ_fold. IPR013069. BTB_POZ. IPR007087. Znf_C2H2. IPR015880. Znf_C2H2-like. IPR013087. Znf_C2H2/integrase_DNA-bd. [Graphical view]
Pfam	PF00651. BTB. 1 hit. PF00096. zf-C2H2. 1 hit. [Graphical view]
SMART	SM00225. BTB. 1 hit. SM00355. ZnF_C2H2. 5 hits. [Graphical view]
SUPFAM	SSF54695. BTB/POZ_fold. 1 hit.
PROSITE	PS50097. BTB. 1 hit. PS00028. ZINC_FINGER_C2H2_1. 5 hits. PS50157. ZINC_FINGER_C2H2_2. 5 hits. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	HIC1. mouse.
NextBio	287857.
SOURCE	Search...

Entry information

Entry name

HIC1_MOUSE

Accession

Primary (citable) accession number: Q9R1Y5
Secondary accession number(s): B1ARH0, Q9R1Y6, Q9R2B0

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 2, 2002
Last sequence update:	December 14, 2011
Last modified:	May 29, 2013
This is version 108 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program