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Q9R1Y5 (HIC1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 115. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Hypermethylated in cancer 1 protein

Short name=Hic-1
Gene names
Name:Hic1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length733 AA.
Sequence statusComplete.
Protein existenceEvidence 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 ACKR3, FGFBP1 and EFNA1. Ref.7 Ref.8

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 processTranscription
Transcription regulation
Wnt signaling pathway
   Cellular componentNucleus
   Coding sequence diversityAlternative splicing
   DomainRepeat
Zinc-finger
   LigandDNA-binding
Metal-binding
Zinc
   Molecular functionDevelopmental protein
Repressor
   PTMAcetylation
Isopeptide bond
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processWnt 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 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-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentchromatin

Inferred from direct assay Ref.7. Source: UniProtKB

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionhistone deacetylase binding

Inferred from sequence or structural similarity. Source: UniProtKB

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

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

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sirt1Q923E42EBI-5236187,EBI-1802585
Tcf7l2Q924A04EBI-5236187,EBI-646713

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 733733Hypermethylated in cancer 1 protein
PRO_0000046943

Regions

Domain47 – 11064BTB
Zinc finger437 – 46428C2H2-type 1
Zinc finger507 – 53428C2H2-type 2
Zinc finger535 – 56228C2H2-type 3
Zinc finger563 – 59028C2H2-type 4
Zinc finger591 – 61828C2H2-type 5
Region154 – 315162Mediates HDAC-dependent transcriptional repression By similarity
Region241 – 2477Interaction with CTBP1 By similarity
Compositional bias1 – 1313Arg/Gly/Pro-rich
Compositional bias112 – 1198Poly-Ala
Compositional bias160 – 1678Poly-Gly
Compositional bias195 – 1995Poly-Pro

Amino acid modifications

Modified residue3331N6-acetyllysine; alternate By similarity
Cross-link333Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate By similarity

Experimental info

Sequence conflict191T → M in AAD30654. Ref.1
Sequence conflict191T → M in AAD30655. Ref.1
Sequence conflict191T → M no nucleotide entry Ref.4
Sequence conflict831N → S in AAD30654. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified December 14, 2011. Version 4.
Checksum: 912C253ED2C25E61

FASTA73376,828
        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 

« Hide

References

« Hide '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. expand/collapse author list , 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]"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.
[9]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.
RefSeqNP_001091673.1. NM_001098203.1.
UniGeneMm.57250.

3D structure databases

ProteinModelPortalQ9R1Y5.
SMRQ9R1Y5. Positions 25-145, 437-613.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid200302. 1 interaction.
IntActQ9R1Y5. 4 interactions.
MINTMINT-2731109.

PTM databases

PhosphoSiteQ9R1Y5.

Proteomic databases

PaxDbQ9R1Y5.
PRIDEQ9R1Y5.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID15248.
KEGGmmu:15248.
UCSCuc007kdc.1. mouse. [Q9R1Y5-1]

Organism-specific databases

CTD3090.
MGIMGI:1338010. Hic1.

Phylogenomic databases

eggNOGCOG5048.
HOGENOMHOG000026793.
HOVERGENHBG031606.
InParanoidB1ARH0.
TreeFamTF333488.

Gene expression databases

ArrayExpressQ9R1Y5.
BgeeQ9R1Y5.
CleanExMM_HIC1.
GenevestigatorQ9R1Y5.

Family and domain databases

Gene3D3.30.160.60. 4 hits.
3.30.710.10. 1 hit.
InterProIPR000210. BTB/POZ-like.
IPR011333. BTB/POZ_fold.
IPR013069. BTB_POZ.
IPR028424. HIC1.
IPR007087. Znf_C2H2.
IPR015880. Znf_C2H2-like.
IPR013087. Znf_C2H2/integrase_DNA-bd.
[Graphical view]
PANTHERPTHR11389:SF322. PTHR11389:SF322. 1 hit.
PfamPF00651. BTB. 1 hit.
PF00096. zf-C2H2. 2 hits.
[Graphical view]
SMARTSM00225. BTB. 1 hit.
SM00355. ZnF_C2H2. 5 hits.
[Graphical view]
SUPFAMSSF54695. SSF54695. 1 hit.
PROSITEPS50097. BTB. 1 hit.
PS00028. ZINC_FINGER_C2H2_1. 5 hits.
PS50157. ZINC_FINGER_C2H2_2. 5 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSHIC1. mouse.
NextBio287857.
PROQ9R1Y5.
SOURCESearch...

Entry information

Entry nameHIC1_MOUSE
AccessionPrimary (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: March 19, 2014
This is version 115 of the entry and version 4 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot