HIC1_MOUSE
ID HIC1_MOUSE Reviewed; 733 AA.
AC Q9R1Y5; B1ARH0; Q9R1Y6; Q9R2B0;
DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 14-DEC-2011, sequence version 4.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=Hypermethylated in cancer 1 protein;
DE Short=Hic-1;
GN Name=Hic1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], NUCLEOTIDE SEQUENCE [MRNA] OF 13-733,
RP AND DEVELOPMENTAL STAGE.
RC STRAIN=129/Sv, and Swiss Webster; TISSUE=Embryo;
RX PubMed=10072440; DOI=10.1093/hmg/8.4.697;
RA Grimm C., Spoerle R., Schmid T.E., Adler I.-D., Adamski J., Schughart K.,
RA Graw J.;
RT "Isolation and embryonic expression of the novel mouse gene Hic1, the
RT homologue of HIC1, a candidate gene for the Miller-Dieker syndrome.";
RL Hum. Mol. Genet. 8:697-710(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE, FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=10655551; DOI=10.1093/hmg/9.3.413;
RA Carter M.G., Johns M.A., Zeng X., Zhou L., Zink M.C., Mankowski J.L.,
RA Donovan D.M., Baylin S.B.;
RT "Mice deficient in the candidate tumor suppressor gene Hic1 exhibit
RT developmental defects of structures affected in the Miller-Dieker
RT syndrome.";
RL Hum. Mol. Genet. 9:413-419(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-20, AND PROMOTER USAGE.
RX PubMed=11073960; DOI=10.1074/jbc.m008690200;
RA Guerardel C., Deltour S., Pinte S., Monte D., Begue A., Godwin A.K.,
RA Leprince D.;
RT "Identification in the human candidate tumor suppressor gene HIC-1 of a new
RT major alternative TATA-less promoter positively regulated by p53.";
RL J. Biol. Chem. 276:3078-3089(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 20-179.
RC STRAIN=129/Sv; TISSUE=Liver;
RX PubMed=10371200; DOI=10.1016/s0014-5793(99)00583-9;
RA Guerardel C., Deltour S., Leprince D.;
RT "Evolutionary divergence in the broad complex, tramtrack and bric a
RT brac/poxviruses and zinc finger domain from the candidate tumor suppressor
RT gene hypermethylated in cancer.";
RL FEBS Lett. 451:253-256(1999).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=12539045; DOI=10.1038/ng1077;
RA Chen W.Y., Zeng X., Carter M.G., Morrell C.N., Chiu Yen R.W., Esteller M.,
RA Watkins D.N., Herman J.G., Mankowski J.L., Baylin S.B.;
RT "Heterozygous disruption of Hic1 predisposes mice to a gender-dependent
RT spectrum of malignant tumors.";
RL Nat. Genet. 33:197-202(2003).
RN [7]
RP FUNCTION, AND INTERACTION WITH SIRT1.
RX PubMed=16269335; DOI=10.1016/j.cell.2005.08.011;
RA Chen W.Y., Wang D.H., Yen R.C., Luo J., Gu W., Baylin S.B.;
RT "Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent
RT DNA-damage responses.";
RL Cell 123:437-448(2005).
RN [8]
RP FUNCTION.
RX PubMed=18347096; DOI=10.1101/gad.1640908;
RA Briggs K.J., Corcoran-Schwartz I.M., Zhang W., Harcke T., Devereux W.L.,
RA Baylin S.B., Eberhart C.G., Watkins D.N.;
RT "Cooperation between the Hic1 and Ptch1 tumor suppressors in
RT medulloblastoma.";
RL Genes Dev. 22:770-785(2008).
RN [9]
RP ERRATUM OF PUBMED:18347096.
RA Briggs K.J., Corcoran-Schwartz I.M., Zhang W., Harcke T., Devereux W.L.,
RA Baylin S.B., Eberhart C.G., Watkins D.N.;
RL Genes Dev. 22:1410-1410(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-704, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [11]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-159, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryo;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
CC -!- FUNCTION: Transcriptional repressor (PubMed:18347096). Recognizes and
CC binds to the consensus sequence '5-[CG]NG[CG]GGGCA[CA]CC-3' (By
CC similarity). May act as a tumor suppressor (PubMed:16269335,
CC PubMed:18347096). Involved in development of head, face, limbs and
CC ventral body wall (PubMed:10655551). Involved in down-regulation of
CC SIRT1 and thereby is involved in regulation of p53/TP53-dependent
CC apoptotic DNA-damage responses (PubMed:16269335). The specific target
CC gene promoter association seems to be depend on corepressors, such as
CC CTBP1 or CTBP2 and MTA1 (By similarity). In cooperation with MTA1
CC (indicative for an association with the NuRD complex) represses
CC transcription from CCND1/cyclin-D1 and CDKN1C/p57Kip2 specifically in
CC quiescent cells (By similarity). Involved in regulation of the Wnt
CC signaling pathway probably by association with TCF7L2 and preventing
CC TCF7L2 and CTNNB1 association with promoters of TCF-responsive genes
CC (By similarity). Seems to repress transcription from E2F1 and ATOH1
CC which involves ARID1A, indicative for the participation of a distinct
CC SWI/SNF-type chromatin-remodeling complex (By similarity). Probably
CC represses transcription from ACKR3, FGFBP1 and EFNA1 (By similarity).
CC {ECO:0000250|UniProtKB:Q14526, ECO:0000269|PubMed:10655551,
CC ECO:0000269|PubMed:16269335, ECO:0000269|PubMed:18347096}.
CC -!- SUBUNIT: Self-associates (By similarity). Interacts with HIC2 (By
CC similarity). Interacts with CTBP1 and CTBP2 (By similarity). Interacts
CC with TCF7L2 and ARID1A (By similarity). Interacts with MTA1 and MBD3;
CC indicative for an association with the NuRD complex (By similarity).
CC Interacts with SIRT1 (PubMed:16269335). {ECO:0000250|UniProtKB:Q14526,
CC ECO:0000269|PubMed:16269335}.
CC -!- INTERACTION:
CC Q9R1Y5; Q923E4: Sirt1; NbExp=2; IntAct=EBI-5236187, EBI-1802585;
CC Q9R1Y5; Q924A0: Tcf7l2; NbExp=4; IntAct=EBI-5236187, EBI-646713;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=1;
CC Comment=A number of isoforms may be produced.;
CC Name=1;
CC IsoId=Q9R1Y5-1; Sequence=Displayed;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed with highest levels in heart
CC and lung. {ECO:0000269|PubMed:10655551}.
CC -!- DEVELOPMENTAL STAGE: Expression is first detected in the embryo after 9
CC dpc. In the embryo, expression is found in restricted regions of somite
CC derivatives, limb anlagen and cranio-facial mesenchyme. In the fetus,
CC it is additionally expressed in mesenchymes apposed to precartilaginous
CC condensations, at many interfaces to budding epithelia of inner organs,
CC and weakly in muscles. {ECO:0000269|PubMed:10072440}.
CC -!- DOMAIN: The BTB domain inhibits the binding to a single consensus
CC binding site, but mediates cooperative binding to multiple binding
CC sites. {ECO:0000250}.
CC -!- PTM: Acetylated on several residues, including Lys-333. Lys-333 is
CC deacetylated by SIRT1 (By similarity). {ECO:0000250}.
CC -!- PTM: Sumoylated on Lys-333 by a PIAS family member, which enhances
CC interaction with MTA1, positively regulates transcriptional repression
CC activity and is enhanced by HDAC4. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Impaired development resulting in embryonic and
CC perinatal lethality (PubMed:10655551, PubMed:12539045). Serious
CC developmental anomalies including acrania, exencephaly, cleft palate,
CC omphalocele and limb abnormalities (PubMed:10655551). Mice disrupted in
CC the germ line for only one allele of Hic1 develop many different
CC spontaneous malignant tumors, including a predominance of epithelial
CC cancers in males and lymphomas and sarcomas in females
CC (PubMed:12539045). The complete loss of Hic1 function in the
CC heterozygous mice seems to involve dense methylation of the promoter of
CC the remaining wild-type allele (PubMed:12539045).
CC {ECO:0000269|PubMed:10655551, ECO:0000269|PubMed:12539045}.
CC -!- SIMILARITY: Belongs to the krueppel C2H2-type zinc-finger protein
CC family. Hic subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD30654.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAD30655.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AF036334; AAD30654.1; ALT_INIT; mRNA.
DR EMBL; AF036582; AAD30655.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL603905; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AJ132691; CAB44493.1; -; Genomic_DNA.
DR RefSeq; NP_001091673.1; NM_001098203.1. [Q9R1Y5-1]
DR AlphaFoldDB; Q9R1Y5; -.
DR SMR; Q9R1Y5; -.
DR BioGRID; 200302; 1.
DR IntAct; Q9R1Y5; 3.
DR MINT; Q9R1Y5; -.
DR STRING; 10090.ENSMUSP00000053483; -.
DR iPTMnet; Q9R1Y5; -.
DR PhosphoSitePlus; Q9R1Y5; -.
DR jPOST; Q9R1Y5; -.
DR MaxQB; Q9R1Y5; -.
DR PaxDb; Q9R1Y5; -.
DR PeptideAtlas; Q9R1Y5; -.
DR PRIDE; Q9R1Y5; -.
DR ProteomicsDB; 269790; -. [Q9R1Y5-1]
DR DNASU; 15248; -.
DR Ensembl; ENSMUST00000131720; ENSMUSP00001091661; ENSMUSG00000043099. [Q9R1Y5-1]
DR GeneID; 15248; -.
DR KEGG; mmu:15248; -.
DR UCSC; uc007kdc.1; mouse. [Q9R1Y5-1]
DR CTD; 3090; -.
DR MGI; MGI:1338010; Hic1.
DR eggNOG; KOG1721; Eukaryota.
DR GeneTree; ENSGT00940000161725; -.
DR InParanoid; Q9R1Y5; -.
DR TreeFam; TF333488; -.
DR Reactome; R-MMU-3232118; SUMOylation of transcription factors.
DR BioGRID-ORCS; 15248; 3 hits in 72 CRISPR screens.
DR ChiTaRS; Hic1; mouse.
DR PRO; PR:Q9R1Y5; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q9R1Y5; protein.
DR GO; GO:0000785; C:chromatin; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; ISO:MGI.
DR GO; GO:0042826; F:histone deacetylase binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IDA:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0043517; P:positive regulation of DNA damage response, signal transduction by p53 class mediator; IMP:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR Gene3D; 3.30.710.10; -; 1.
DR InterPro; IPR000210; BTB/POZ_dom.
DR InterPro; IPR028424; HIC1.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR InterPro; IPR036236; Znf_C2H2_sf.
DR InterPro; IPR013087; Znf_C2H2_type.
DR PANTHER; PTHR24390:SF145; PTHR24390:SF145; 1.
DR Pfam; PF00651; BTB; 1.
DR Pfam; PF00096; zf-C2H2; 4.
DR SMART; SM00225; BTB; 1.
DR SMART; SM00355; ZnF_C2H2; 5.
DR SUPFAM; SSF54695; SSF54695; 1.
DR SUPFAM; SSF57667; SSF57667; 3.
DR PROSITE; PS50097; BTB; 1.
DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 5.
DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 5.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Developmental protein; DNA-binding;
KW Isopeptide bond; Metal-binding; Methylation; Nucleus; Phosphoprotein;
KW Reference proteome; Repeat; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation; Wnt signaling pathway; Zinc;
KW Zinc-finger.
FT CHAIN 1..733
FT /note="Hypermethylated in cancer 1 protein"
FT /id="PRO_0000046943"
FT DOMAIN 47..110
FT /note="BTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT ZN_FING 437..464
FT /note="C2H2-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT ZN_FING 507..534
FT /note="C2H2-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT ZN_FING 535..562
FT /note="C2H2-type 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT ZN_FING 563..590
FT /note="C2H2-type 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT ZN_FING 591..618
FT /note="C2H2-type 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT REGION 154..315
FT /note="Mediates HDAC-dependent transcriptional repression"
FT /evidence="ECO:0000250"
FT REGION 189..209
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 241..421
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 241..247
FT /note="Interaction with CTBP1"
FT /evidence="ECO:0000250"
FT COMPBIAS 190..205
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 283..297
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 347..361
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 369..383
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 159
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 237
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14526"
FT MOD_RES 248
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14526"
FT MOD_RES 333
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q14526"
FT MOD_RES 366
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14526"
FT MOD_RES 704
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CROSSLNK 333
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250"
FT CONFLICT 19
FT /note="T -> M (in Ref. 1; AAD30654/AAD30655 and 4; no
FT nucleotide entry)"
FT /evidence="ECO:0000305"
FT CONFLICT 83
FT /note="N -> S (in Ref. 1; AAD30654)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 733 AA; 76828 MW; 912C253ED2C25E61 CRC64;
MTFPEADILL KSGECAGQTM LDTMEAPGHS RQLLLQLNNQ RTKGFLCDVI IVVQNALFRA
HKNVLAASSA YLKSLVVHDN LLNLDHDMVS PAVFRLVLDF IYTGRLTDSV EAAAAAAVAP
GAEPSLGAVL AAASYLQIPD LVALCKKRLK RHGKYCHLRG GGSGGGGYAP YGRPGRGLRA
ATPVIQACYS SPAGPPPPPA AEPPSGPDAA VNTHCAELYA SGPGPAASLC APERRCSPLC
GLDLSKKSPP GSSVPERPLS ERELPPRPDS PPGAGPAVYK EPSLALPPLP PLPFQKLEEA
VPTPDPFRGS GGSPGPEPPG RPDGSSLLYR WMKHEPGLGS YGDELVRDRG SPGERLEERG
GDPAASPGGP PLGLVPPPRY PGSLDGPGTG ADGDDYKSSS EETGSSEDPS PPGGHLEGYP
CPHLAYGEPE SFGDNLYVCI PCGKGFPSSE QLNAHVEAHV EEEEALYGRA EAAEVAAGAA
GLGPPFGGGG DKVTGAPGGL GELLRPYRCA SCDKSYKDPA TLRQHEKTHW LTRPYPCTIC
GKKFTQRGTM TRHMRSHLGL KPFACDACGM RFTRQYRLTE HMRIHSGEKP YECQVCGGKF
AQQRNLISHM KMHAVGGAAG AAGALAGLGG LPGVPGPDGK GKLDFPEGVF AVARLTAEQL
SLKQQDKAAA AELLAQTTHF LHDPKVALES LYPLAKFTAE LGLSPDKAAE VLSQGAHLAA
GPDSRTIDRF SPT
