CDN1C_HUMAN
ID CDN1C_HUMAN Reviewed; 316 AA.
AC P49918;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=Cyclin-dependent kinase inhibitor 1C;
DE AltName: Full=Cyclin-dependent kinase inhibitor p57;
DE AltName: Full=p57Kip2;
GN Name=CDKN1C; Synonyms=KIP2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
RC TISSUE=Embryo;
RX PubMed=7729684; DOI=10.1101/gad.9.6.650;
RA Matsuoka S., Edwards M.C., Bai C., Parker S., Zhang P., Baldini A.,
RA Harper J.W., Elledge S.J.;
RT "p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor
RT family, is a candidate tumor suppressor gene.";
RL Genes Dev. 9:650-662(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8640800;
RA Reid L.H., Crider-Miller S.J., West A., Lee M.H., Massague J.,
RA Weissman B.E.;
RT "Genomic organization of the human p57KIP2 gene and its analysis in the
RT G401 Wilms' tumor assay.";
RL Cancer Res. 56:1214-1218(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG).
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 12-316, AND VARIANTS.
RX PubMed=8655143; DOI=10.1007/bf02281873;
RA Tokino T., Urano T., Furuhata T., Matsushima M., Miyatsu T., Sasaki S.,
RA Nakamura Y.;
RT "Characterization of the human p57KIP2 gene: alternative splicing,
RT insertion/deletion polymorphisms in VNTR sequences in the coding region,
RT and mutational analysis.";
RL Hum. Genet. 97:625-631(1996).
RN [5]
RP INVOLVEMENT IN BWS.
RX PubMed=10424811;
RA Lam W.W.K., Hatada I., Ohishi S., Mukai T., Joyce J.A., Cole T.R.P.,
RA Donnai D., Reik W., Schofield P.N., Maher E.R.;
RT "Analysis of germline CDKN1C (p57-KIP2) mutations in familial and sporadic
RT Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype
RT correlation.";
RL J. Med. Genet. 36:518-523(1999).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-268, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [7]
RP TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, INTERACTION WITH PCNA, VARIANTS
RP IMAGE ASN-274; SER-276; VAL-276; GLU-278 AND PRO-279, AND CHARACTERIZATION
RP OF VARIANTS IMAGE SER-276 AND GLU-278.
RX PubMed=22634751; DOI=10.1038/ng.2275;
RA Arboleda V.A., Lee H., Parnaik R., Fleming A., Banerjee A.,
RA Ferraz-de-Souza B., Delot E.C., Rodriguez-Fernandez I.A., Braslavsky D.,
RA Bergada I., Dell'Angelica E.C., Nelson S.F., Martinez-Agosto J.A.,
RA Achermann J.C., Vilain E.;
RT "Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.";
RL Nat. Genet. 44:788-792(2012).
RN [8]
RP VARIANTS BWS LEU-12; PRO-53; ASP-64 DEL; LEU-70; ALA-158 AND PRO-ALA-215
RP INS, AND PATERNAL IMPRINTING.
RX PubMed=26077438; DOI=10.1002/humu.22824;
RA Brioude F., Netchine I., Praz F., Le Jule M., Calmel C., Lacombe D.,
RA Edery P., Catala M., Odent S., Isidor B., Lyonnet S., Sigaudy S.,
RA Leheup B., Audebert-Bellanger S., Burglen L., Giuliano F., Alessandri J.L.,
RA Cormier-Daire V., Laffargue F., Blesson S., Coupier I., Lespinasse J.,
RA Blanchet P., Boute O., Baumann C., Polak M., Doray B., Verloes A., Viot G.,
RA Le Bouc Y., Rossignol S.;
RT "Mutations of the imprinted CDKN1C gene as a cause of the overgrowth
RT Beckwith-Wiedemann syndrome: clinical spectrum and functional
RT characterization.";
RL Hum. Mutat. 36:894-902(2015).
CC -!- FUNCTION: Potent tight-binding inhibitor of several G1 cyclin/CDK
CC complexes (cyclin E-CDK2, cyclin D2-CDK4, and cyclin A-CDK2) and, to
CC lesser extent, of the mitotic cyclin B-CDC2. Negative regulator of cell
CC proliferation. May play a role in maintenance of the non-proliferative
CC state throughout life.
CC -!- SUBUNIT: Interacts with PCNA. {ECO:0000269|PubMed:22634751}.
CC -!- INTERACTION:
CC P49918; Q9NXK8: FBXL12; NbExp=6; IntAct=EBI-519256, EBI-719790;
CC P49918; P33993: MCM7; NbExp=2; IntAct=EBI-519256, EBI-355924;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=P49918-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=P49918-2; Sequence=VSP_000867;
CC -!- TISSUE SPECIFICITY: Expressed in the heart, brain, lung, skeletal
CC muscle, kidney, pancreas and testis. Expressed in the eye. High levels
CC are seen in the placenta while low levels are seen in the liver.
CC {ECO:0000269|PubMed:22634751}.
CC -!- DEVELOPMENTAL STAGE: Expressed within a subset of cells in the
CC subcapsular or developing definitive zone of the adrenal gland.
CC {ECO:0000269|PubMed:22634751}.
CC -!- DISEASE: Beckwith-Wiedemann syndrome (BWS) [MIM:130650]: A disorder
CC characterized by anterior abdominal wall defects including exomphalos
CC (omphalocele), pre- and postnatal overgrowth, and macroglossia.
CC Additional less frequent complications include specific developmental
CC defects and a predisposition to embryonal tumors.
CC {ECO:0000269|PubMed:10424811, ECO:0000269|PubMed:26077438}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Intrauterine growth retardation, metaphyseal dysplasia,
CC adrenal hypoplasia congenita, and genital anomalies (IMAGE)
CC [MIM:614732]: A rare condition characterized by intrauterine growth
CC restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and
CC genital anomalies. Patients with this condition may present shortly
CC after birth with severe adrenal insufficiency, which can be life-
CC threatening if not recognized early and commenced on steroid
CC replacement therapy. Other reported features in this condition include,
CC hypercalciuria and/or hypercalcemia, craniosynostosis, cleft palate,
CC and scoliosis. {ECO:0000269|PubMed:22634751}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Paternally imprinted, therefore most expression comes
CC from the maternal allele. {ECO:0000305|PubMed:26077438}.
CC -!- SIMILARITY: Belongs to the CDI family. {ECO:0000305}.
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DR EMBL; U22398; AAA85095.1; -; mRNA.
DR EMBL; U48869; AAB05896.1; -; Genomic_DNA.
DR EMBL; BC067842; AAH67842.1; -; mRNA.
DR EMBL; D64137; BAA11014.1; -; Genomic_DNA.
DR EMBL; D64137; BAA11015.1; -; Genomic_DNA.
DR CCDS; CCDS44519.1; -. [P49918-2]
DR CCDS; CCDS7738.1; -. [P49918-1]
DR PIR; G02424; G02424.
DR RefSeq; NP_000067.1; NM_000076.2. [P49918-1]
DR RefSeq; NP_001116102.1; NM_001122630.1. [P49918-2]
DR RefSeq; NP_001116103.1; NM_001122631.1. [P49918-2]
DR RefSeq; XP_016872577.1; XM_017017088.1.
DR AlphaFoldDB; P49918; -.
DR BioGRID; 107462; 37.
DR ELM; P49918; -.
DR IntAct; P49918; 14.
DR MINT; P49918; -.
DR STRING; 9606.ENSP00000413720; -.
DR iPTMnet; P49918; -.
DR PhosphoSitePlus; P49918; -.
DR BioMuta; CDKN1C; -.
DR DMDM; 1705731; -.
DR EPD; P49918; -.
DR jPOST; P49918; -.
DR MassIVE; P49918; -.
DR MaxQB; P49918; -.
DR PaxDb; P49918; -.
DR PeptideAtlas; P49918; -.
DR PRIDE; P49918; -.
DR ProteomicsDB; 56184; -. [P49918-1]
DR ProteomicsDB; 56185; -. [P49918-2]
DR Antibodypedia; 972; 1164 antibodies from 41 providers.
DR DNASU; 1028; -.
DR Ensembl; ENST00000414822.8; ENSP00000413720.3; ENSG00000129757.15. [P49918-1]
DR Ensembl; ENST00000430149.3; ENSP00000411552.2; ENSG00000129757.15. [P49918-1]
DR Ensembl; ENST00000440480.8; ENSP00000411257.2; ENSG00000129757.15. [P49918-2]
DR GeneID; 1028; -.
DR KEGG; hsa:1028; -.
DR MANE-Select; ENST00000440480.8; ENSP00000411257.2; NM_001122630.2; NP_001116102.1. [P49918-2]
DR UCSC; uc001lwr.5; human. [P49918-1]
DR CTD; 1028; -.
DR DisGeNET; 1028; -.
DR GeneCards; CDKN1C; -.
DR GeneReviews; CDKN1C; -.
DR HGNC; HGNC:1786; CDKN1C.
DR HPA; ENSG00000129757; Tissue enhanced (ovary).
DR MalaCards; CDKN1C; -.
DR MIM; 130650; phenotype.
DR MIM; 600856; gene.
DR MIM; 614732; phenotype.
DR neXtProt; NX_P49918; -.
DR OpenTargets; ENSG00000129757; -.
DR Orphanet; 231120; Beckwith-Wiedemann syndrome due to CDKN1C mutation.
DR Orphanet; 85173; IMAGe syndrome.
DR Orphanet; 436144; Intrauterine growth restriction-short stature-early adult-onset diabetes syndrome.
DR Orphanet; 397590; Silver-Russell syndrome due to a point mutation.
DR PharmGKB; PA26320; -.
DR VEuPathDB; HostDB:ENSG00000129757; -.
DR eggNOG; KOG4743; Eukaryota.
DR GeneTree; ENSGT00940000162677; -.
DR HOGENOM; CLU_077692_0_0_1; -.
DR InParanoid; P49918; -.
DR OMA; NNTHITD; -.
DR OrthoDB; 1595421at2759; -.
DR PhylomeDB; P49918; -.
DR TreeFam; TF101111; -.
DR PathwayCommons; P49918; -.
DR Reactome; R-HSA-69231; Cyclin D associated events in G1.
DR Reactome; R-HSA-9661069; Defective binding of RB1 mutants to E2F1,(E2F2, E2F3).
DR SignaLink; P49918; -.
DR SIGNOR; P49918; -.
DR BioGRID-ORCS; 1028; 24 hits in 1094 CRISPR screens.
DR ChiTaRS; CDKN1C; human.
DR GeneWiki; Cyclin-dependent_kinase_inhibitor_1C; -.
DR GenomeRNAi; 1028; -.
DR Pharos; P49918; Tbio.
DR PRO; PR:P49918; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P49918; protein.
DR Bgee; ENSG00000129757; Expressed in placenta and 93 other tissues.
DR ExpressionAtlas; P49918; baseline and differential.
DR Genevisible; P49918; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; IEA:InterPro.
DR GO; GO:0004860; F:protein kinase inhibitor activity; IMP:CAFA.
DR GO; GO:0044877; F:protein-containing complex binding; IPI:CAFA.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:1904030; P:negative regulation of cyclin-dependent protein kinase activity; IMP:CAFA.
DR GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; IMP:BHF-UCL.
DR GO; GO:0033673; P:negative regulation of kinase activity; IDA:UniProtKB.
DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IBA:GO_Central.
DR GO; GO:0042326; P:negative regulation of phosphorylation; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IGI:UniProtKB.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IMP:BHF-UCL.
DR DisProt; DP00017; -.
DR Gene3D; 4.10.365.10; -; 1.
DR InterPro; IPR003175; CDI_dom.
DR InterPro; IPR044898; CDI_dom_sf.
DR InterPro; IPR029842; CDKN1C.
DR PANTHER; PTHR10265:SF44; PTHR10265:SF44; 1.
DR Pfam; PF02234; CDI; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell cycle; Disease variant; Methylation; Nucleus;
KW Phosphoprotein; Protein kinase inhibitor; Reference proteome; Repeat;
KW Tumor suppressor.
FT CHAIN 1..316
FT /note="Cyclin-dependent kinase inhibitor 1C"
FT /id="PRO_0000190087"
FT REPEAT 156..159
FT /note="1"
FT REPEAT 160..163
FT /note="2"
FT REPEAT 180..183
FT /note="3"
FT REPEAT 184..187
FT /note="4"
FT REPEAT 188..191
FT /note="5"
FT REPEAT 198..201
FT /note="6"
FT REPEAT 202..205
FT /note="7"
FT REPEAT 206..209
FT /note="8"
FT REPEAT 210..213
FT /note="9"
FT REGION 124..153
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 156..213
FT /note="9 X 4 AA repeats of P-A-P-A"
FT REGION 181..260
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 278..316
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 278..281
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 137..153
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 181..217
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 223..237
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 107
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:P49919"
FT MOD_RES 268
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT VAR_SEQ 1..11
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000305"
FT /id="VSP_000867"
FT VARIANT 12
FT /note="M -> L (in BWS; unknown pathological significance;
FT dbSNP:rs483352966)"
FT /evidence="ECO:0000269|PubMed:26077438"
FT /id="VAR_075200"
FT VARIANT 53
FT /note="L -> P (in BWS; dbSNP:rs483352968)"
FT /evidence="ECO:0000269|PubMed:26077438"
FT /id="VAR_075201"
FT VARIANT 64
FT /note="Missing (in BWS; dbSNP:rs483352969)"
FT /evidence="ECO:0000269|PubMed:26077438"
FT /id="VAR_075202"
FT VARIANT 70
FT /note="P -> L (in BWS; dbSNP:rs483352970)"
FT /evidence="ECO:0000269|PubMed:26077438"
FT /id="VAR_075203"
FT VARIANT 158
FT /note="P -> A (in BWS; unknown pathological significance;
FT dbSNP:rs483352981)"
FT /evidence="ECO:0000269|PubMed:26077438"
FT /id="VAR_075204"
FT VARIANT 171..174
FT /note="Missing (in several cancers)"
FT /id="VAR_001404"
FT VARIANT 181..184
FT /note="Missing (in hepatocellular carcinomas)"
FT /id="VAR_001405"
FT VARIANT 200..203
FT /note="Missing (in a bladder cancer)"
FT /id="VAR_001406"
FT VARIANT 206..209
FT /note="Missing (in a breast cancer)"
FT /id="VAR_001407"
FT VARIANT 215
FT /note="A -> APA (in BWS; dbSNP:rs772704243)"
FT /evidence="ECO:0000269|PubMed:26077438"
FT /id="VAR_075205"
FT VARIANT 274
FT /note="D -> N (in IMAGE; dbSNP:rs387907225)"
FT /evidence="ECO:0000269|PubMed:22634751"
FT /id="VAR_068848"
FT VARIANT 276
FT /note="F -> S (in IMAGE; PCNA binding is disrupted;
FT dbSNP:rs387907224)"
FT /evidence="ECO:0000269|PubMed:22634751"
FT /id="VAR_068849"
FT VARIANT 276
FT /note="F -> V (in IMAGE; dbSNP:rs387907223)"
FT /evidence="ECO:0000269|PubMed:22634751"
FT /id="VAR_068850"
FT VARIANT 278
FT /note="K -> E (in IMAGE; PCNA binding is disrupted;
FT dbSNP:rs387907226)"
FT /evidence="ECO:0000269|PubMed:22634751"
FT /id="VAR_068851"
FT VARIANT 279
FT /note="R -> P (in IMAGE; dbSNP:rs318240750)"
FT /evidence="ECO:0000269|PubMed:22634751"
FT /id="VAR_068852"
SQ SEQUENCE 316 AA; 32177 MW; A94CCBF09F8CB3E4 CRC64;
MSDASLRSTS TMERLVARGT FPVLVRTSAC RSLFGPVDHE ELSRELQARL AELNAEDQNR
WDYDFQQDMP LRGPGRLQWT EVDSDSVPAF YRETVQVGRC RLLLAPRPVA VAVAVSPPLE
PAAESLDGLE EAPEQLPSVP VPAPASTPPP VPVLAPAPAP APAPVAAPVA APVAVAVLAP
APAPAPAPAP APAPVAAPAP APAPAPAPAP APAPAPDAAP QESAEQGANQ GQRGQEPLAD
QLHSGISGRP AAGTAAASAN GAAIKKLSGP LISDFFAKRK RSAPEKSSGD VPAPCPSPSA
APGVGSVEQT PRKRLR
