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Q9R1Y5

- HIC1_MOUSE

UniProt

Q9R1Y5 - HIC1_MOUSE

Protein

Hypermethylated in cancer 1 protein

Gene

Hic1

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 118 (01 Oct 2014)
      Sequence version 4 (14 Dec 2011)
      Previous versions | rss
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    Functioni

    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 EFNA1.2 Publications

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Zinc fingeri437 – 46428C2H2-type 1PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri507 – 53428C2H2-type 2PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri535 – 56228C2H2-type 3PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri563 – 59028C2H2-type 4PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri591 – 61828C2H2-type 5PROSITE-ProRule annotationAdd
    BLAST

    GO - Molecular functioni

    1. histone deacetylase binding Source: UniProtKB
    2. metal ion binding Source: UniProtKB-KW
    3. protein binding Source: IntAct
    4. sequence-specific DNA binding Source: UniProtKB
    5. sequence-specific DNA binding transcription factor activity Source: UniProtKB

    GO - Biological processi

    1. intrinsic apoptotic signaling pathway in response to DNA damage Source: UniProtKB
    2. multicellular organismal development Source: UniProtKB-KW
    3. negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    4. negative regulation of Wnt signaling pathway Source: UniProtKB
    5. positive regulation of DNA damage response, signal transduction by p53 class mediator Source: UniProtKB
    6. transcription, DNA-templated Source: UniProtKB-KW
    7. Wnt signaling pathway Source: UniProtKB-KW

    Keywords - Molecular functioni

    Developmental protein, Repressor

    Keywords - Biological processi

    Transcription, Transcription regulation, Wnt signaling pathway

    Keywords - Ligandi

    DNA-binding, Metal-binding, Zinc

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Hypermethylated in cancer 1 protein
    Short name:
    Hic-1
    Gene namesi
    Name:Hic1
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Unplaced

    Organism-specific databases

    MGIiMGI:1338010. Hic1.

    Subcellular locationi

    Nucleus Curated

    GO - Cellular componenti

    1. chromatin Source: UniProtKB
    2. nucleus Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Defects in Hic1 are the cause of perinatal death with serious developmental anomalies, including acrania, exencephaly, cleft palate, omphalocele, craniofacial and limb anomalies.1 Publication

    Disruption phenotypei

    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.1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 733733Hypermethylated in cancer 1 proteinPRO_0000046943Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei333 – 3331N6-acetyllysine; alternateBy similarity
    Cross-linki333 – 333Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternateBy similarity

    Post-translational modificationi

    Acetylated on several residues, including Lys-333. Lys-333 is deacetylated by SIRT1 By similarity.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

    Keywords - PTMi

    Acetylation, Isopeptide bond, Ubl conjugation

    Proteomic databases

    PaxDbiQ9R1Y5.
    PRIDEiQ9R1Y5.

    PTM databases

    PhosphoSiteiQ9R1Y5.

    Expressioni

    Tissue specificityi

    Ubiquitously expressed with highest levels in heart and lung.1 Publication

    Developmental stagei

    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.1 Publication

    Gene expression databases

    ArrayExpressiQ9R1Y5.
    BgeeiQ9R1Y5.
    CleanExiMM_HIC1.
    GenevestigatoriQ9R1Y5.

    Interactioni

    Subunit structurei

    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.By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    Sirt1Q923E42EBI-5236187,EBI-1802585
    Tcf7l2Q924A04EBI-5236187,EBI-646713

    Protein-protein interaction databases

    BioGridi200302. 1 interaction.
    IntActiQ9R1Y5. 4 interactions.
    MINTiMINT-2731109.

    Structurei

    3D structure databases

    ProteinModelPortaliQ9R1Y5.
    SMRiQ9R1Y5. Positions 25-145, 429-613.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini47 – 11064BTBPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni154 – 315162Mediates HDAC-dependent transcriptional repressionBy similarityAdd
    BLAST
    Regioni241 – 2477Interaction with CTBP1By similarity

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi1 – 1313Arg/Gly/Pro-richAdd
    BLAST
    Compositional biasi112 – 1198Poly-Ala
    Compositional biasi160 – 1678Poly-Gly
    Compositional biasi195 – 1995Poly-Pro

    Domaini

    The BTB domain inhibits the binding to a single consensus binding site, but mediates cooperative binding to multiple binding sites.By similarity

    Sequence similaritiesi

    Contains 1 BTB (POZ) domain.PROSITE-ProRule annotation
    Contains 5 C2H2-type zinc fingers.PROSITE-ProRule annotation

    Zinc finger

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Zinc fingeri437 – 46428C2H2-type 1PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri507 – 53428C2H2-type 2PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri535 – 56228C2H2-type 3PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri563 – 59028C2H2-type 4PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri591 – 61828C2H2-type 5PROSITE-ProRule annotationAdd
    BLAST

    Keywords - Domaini

    Repeat, Zinc-finger

    Phylogenomic databases

    eggNOGiCOG5048.
    HOGENOMiHOG000026793.
    HOVERGENiHBG031606.
    InParanoidiB1ARH0.
    TreeFamiTF333488.

    Family and domain databases

    Gene3Di3.30.160.60. 4 hits.
    3.30.710.10. 1 hit.
    InterProiIPR000210. 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]
    PANTHERiPTHR11389:SF322. PTHR11389:SF322. 1 hit.
    PfamiPF00651. BTB. 1 hit.
    PF00096. zf-C2H2. 2 hits.
    [Graphical view]
    SMARTiSM00225. BTB. 1 hit.
    SM00355. ZnF_C2H2. 5 hits.
    [Graphical view]
    SUPFAMiSSF54695. SSF54695. 1 hit.
    PROSITEiPS50097. BTB. 1 hit.
    PS00028. ZINC_FINGER_C2H2_1. 5 hits.
    PS50157. ZINC_FINGER_C2H2_2. 5 hits.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    This entry describes 1 isoform i produced by alternative splicing. Align

    Note: A number of isoforms may be produced.

    Isoform 1 (identifier: Q9R1Y5-1) [UniParc]FASTAAdd to Basket

    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.

    « Hide

    MTFPEADILL KSGECAGQTM LDTMEAPGHS RQLLLQLNNQ RTKGFLCDVI    50
    IVVQNALFRA HKNVLAASSA YLKSLVVHDN LLNLDHDMVS PAVFRLVLDF 100
    IYTGRLTDSV EAAAAAAVAP GAEPSLGAVL AAASYLQIPD LVALCKKRLK 150
    RHGKYCHLRG GGSGGGGYAP YGRPGRGLRA ATPVIQACYS SPAGPPPPPA 200
    AEPPSGPDAA VNTHCAELYA SGPGPAASLC APERRCSPLC GLDLSKKSPP 250
    GSSVPERPLS ERELPPRPDS PPGAGPAVYK EPSLALPPLP PLPFQKLEEA 300
    VPTPDPFRGS GGSPGPEPPG RPDGSSLLYR WMKHEPGLGS YGDELVRDRG 350
    SPGERLEERG GDPAASPGGP PLGLVPPPRY PGSLDGPGTG ADGDDYKSSS 400
    EETGSSEDPS PPGGHLEGYP CPHLAYGEPE SFGDNLYVCI PCGKGFPSSE 450
    QLNAHVEAHV EEEEALYGRA EAAEVAAGAA GLGPPFGGGG DKVTGAPGGL 500
    GELLRPYRCA SCDKSYKDPA TLRQHEKTHW LTRPYPCTIC GKKFTQRGTM 550
    TRHMRSHLGL KPFACDACGM RFTRQYRLTE HMRIHSGEKP YECQVCGGKF 600
    AQQRNLISHM KMHAVGGAAG AAGALAGLGG LPGVPGPDGK GKLDFPEGVF 650
    AVARLTAEQL SLKQQDKAAA AELLAQTTHF LHDPKVALES LYPLAKFTAE 700
    LGLSPDKAAE VLSQGAHLAA GPDSRTIDRF SPT 733
    Length:733
    Mass (Da):76,828
    Last modified:December 14, 2011 - v4
    Checksum:i912C253ED2C25E61
    GO

    Sequence cautioni

    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.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti19 – 191T → M in AAD30654. (PubMed:10072440)Curated
    Sequence conflicti19 – 191T → M in AAD30655. (PubMed:10072440)Curated
    Sequence conflicti19 – 191T → M no nucleotide entry (PubMed:11073960)Curated
    Sequence conflicti83 – 831N → S in AAD30654. (PubMed:10072440)Curated

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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.
    RefSeqiNP_001091673.1. NM_001098203.1. [Q9R1Y5-1]
    UniGeneiMm.57250.

    Genome annotation databases

    GeneIDi15248.
    KEGGimmu:15248.
    UCSCiuc007kdc.1. mouse. [Q9R1Y5-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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 .
    RefSeqi NP_001091673.1. NM_001098203.1. [Q9R1Y5-1 ]
    UniGenei Mm.57250.

    3D structure databases

    ProteinModelPortali Q9R1Y5.
    SMRi Q9R1Y5. Positions 25-145, 429-613.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 200302. 1 interaction.
    IntActi Q9R1Y5. 4 interactions.
    MINTi MINT-2731109.

    PTM databases

    PhosphoSitei Q9R1Y5.

    Proteomic databases

    PaxDbi Q9R1Y5.
    PRIDEi Q9R1Y5.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    GeneIDi 15248.
    KEGGi mmu:15248.
    UCSCi uc007kdc.1. mouse. [Q9R1Y5-1 ]

    Organism-specific databases

    CTDi 3090.
    MGIi MGI:1338010. Hic1.

    Phylogenomic databases

    eggNOGi COG5048.
    HOGENOMi HOG000026793.
    HOVERGENi HBG031606.
    InParanoidi B1ARH0.
    TreeFami TF333488.

    Miscellaneous databases

    ChiTaRSi HIC1. mouse.
    NextBioi 287857.
    PROi Q9R1Y5.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q9R1Y5.
    Bgeei Q9R1Y5.
    CleanExi MM_HIC1.
    Genevestigatori Q9R1Y5.

    Family and domain databases

    Gene3Di 3.30.160.60. 4 hits.
    3.30.710.10. 1 hit.
    InterProi IPR000210. 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 ]
    PANTHERi PTHR11389:SF322. PTHR11389:SF322. 1 hit.
    Pfami PF00651. BTB. 1 hit.
    PF00096. zf-C2H2. 2 hits.
    [Graphical view ]
    SMARTi SM00225. BTB. 1 hit.
    SM00355. ZnF_C2H2. 5 hits.
    [Graphical view ]
    SUPFAMi SSF54695. SSF54695. 1 hit.
    PROSITEi PS50097. BTB. 1 hit.
    PS00028. ZINC_FINGER_C2H2_1. 5 hits.
    PS50157. ZINC_FINGER_C2H2_2. 5 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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. 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.

    Entry informationi

    Entry nameiHIC1_MOUSE
    AccessioniPrimary (citable) accession number: Q9R1Y5
    Secondary accession number(s): B1ARH0, Q9R1Y6, Q9R2B0
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: May 2, 2002
    Last sequence update: December 14, 2011
    Last modified: October 1, 2014
    This is version 118 of the entry and version 4 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3