{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"P38936","secondaryAccessions":["Q14010","Q6FI05","Q9BUT4"],"uniProtkbId":"CDN1A_HUMAN","entryAudit":{"firstPublicDate":"1995-02-01","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2007-01-23","entryVersion":255,"sequenceVersion":3},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"Cyclin-dependent kinase inhibitor 1"}},"alternativeNames":[{"fullName":{"value":"CDK-interacting protein 1"}},{"fullName":{"value":"Melanoma differentiation-associated protein 6"},"shortNames":[{"value":"MDA-6"}]},{"fullName":{"value":"p21"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:1784"}],"value":"CDKN1A"},"synonyms":[{"value":"CAP20"},{"value":"CDKN1"},{"value":"CIP1"},{"value":"MDA6"},{"value":"PIC1"},{"value":"SDI1"},{"value":"WAF1"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P39689"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11595739"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8242751"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9106657"}],"value":"Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest (PubMed:9106657). Involved in p53/TP53 mediated inhibition of cellular proliferation in response to DNA damage. Also involved in p53-independent DNA damage-induced G2 arrest mediated by CREB3L1 in astrocytes and osteoblasts (By similarity). Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (PubMed:11595739). Negatively regulates the CDK4- and CDK6-driven phosphorylation of RB1 in keratinocytes, thereby resulting in the release of E2F1 and subsequent transcription of E2F1-driven G1/S phase promoting genes (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P39689"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11350925"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11595739"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12431783"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18703516"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18794347"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19445729"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19536131"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23213251"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25329316"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8861913"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9106657"}],"value":"Interacts with HDAC1; the interaction is prevented by competitive binding of C10orf90/FATS to HDAC1 facilitating acetylation and protein stabilization of CDKN1A/p21 (By similarity). Interacts with MKRN1 (PubMed:19536131). Interacts with PSMA3 (PubMed:11350925). Interacts with PCNA (PubMed:11595739, PubMed:18703516, PubMed:18794347, PubMed:8861913). Component of the ternary complex, cyclin D-CDK4-CDKN1A. Interacts (via its N-terminal domain) with CDK4; the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4 (PubMed:9106657). Binding to CDK2 leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair (PubMed:19445729). Interacts with PIM1 (PubMed:12431783). Interacts with STK11 and NUAK1 (PubMed:25329316). Interacts wih DTL (PubMed:23213251). Interacts with isoform 1 and isoform 2 of TRIM39 (PubMed:23213251). Interacts with PKP3; the interaction sequesters CDKN1A to the cytoplasm thereby repressing its role as an inhibitor of CDK4- and CDK6-driven RB1 phosphorylation (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P78396","geneName":"CCNA1","intActId":"EBI-375065"},"numberOfExperiments":8,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P20248","geneName":"CCNA2","intActId":"EBI-457097"},"numberOfExperiments":8,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"O95067","geneName":"CCNB2","intActId":"EBI-375024"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P24385","geneName":"CCND1","intActId":"EBI-375001"},"numberOfExperiments":26,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P30279","geneName":"CCND2","intActId":"EBI-748789"},"numberOfExperiments":19,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P30281","geneName":"CCND3","intActId":"EBI-375013"},"numberOfExperiments":29,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P24864","geneName":"CCNE1","intActId":"EBI-519526"},"numberOfExperiments":11,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"O96020","geneName":"CCNE2","intActId":"EBI-375033"},"numberOfExperiments":8,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"O75419","geneName":"CDC45","intActId":"EBI-374969"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"Q99741","geneName":"CDC6","intActId":"EBI-374862"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P06493","geneName":"CDK1","intActId":"EBI-444308"},"numberOfExperiments":10,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"O94921","geneName":"CDK14","intActId":"EBI-1043945"},"numberOfExperiments":11,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P24941","geneName":"CDK2","intActId":"EBI-375096"},"numberOfExperiments":32,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"Q00526","geneName":"CDK3","intActId":"EBI-1245761"},"numberOfExperiments":8,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P11802","geneName":"CDK4","intActId":"EBI-295644"},"numberOfExperiments":10,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"Q00535","geneName":"CDK5","intActId":"EBI-1041567"},"numberOfExperiments":7,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"Q00534","geneName":"CDK6","intActId":"EBI-295663"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"G5E9A7","geneName":"DMWD","intActId":"EBI-10976677"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P41091","geneName":"EIF2S3","intActId":"EBI-1054228"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"O75460-2","geneName":"ERN1","intActId":"EBI-25852368"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"P22607","geneName":"FGFR3","intActId":"EBI-348399"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"Q0VDC6","geneName":"FKBP1A","intActId":"EBI-10226858"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P38936","intActId":"EBI-375077"},"interactantTwo":{"uniProtKBAccession":"Q9BVV2","geneName":"FNDC11","intActId":"EBI-744935"},"numberOfExperiments":3,"or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LOCATION","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11463845"}],"value":"Cytoplasm","id":"SL-0086"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11463845"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23213251"}],"value":"Nucleus","id":"SL-0191"}}]},{"texts":[{"value":"Expressed in all adult tissues, with 5-fold lower levels observed in the brain"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8242751"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8242752"}],"value":"Activated by p53/TP53, mezerein (antileukemic compound) and IFNB1. Repressed by HDAC1"}],"commentType":"INDUCTION"},{"texts":[{"value":"The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment of the DCX(DTL) complex: while the PIP-box interacts with PCNA, the presence of the K+4 submotif, recruits the DCX(DTL) complex, leading to its ubiquitination"}],"commentType":"DOMAIN"},{"texts":[{"value":"The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10753973"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11463845"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12431783"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16982699"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18794347"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20307683"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25329316"}],"value":"Phosphorylation of Thr-145 by Akt or of Ser-146 by PKC impairs binding to PCNA. Phosphorylation at Ser-114 by GSK3-beta enhances ubiquitination by the DCX(DTL) complex. Phosphorylation of Thr-145 by PIM2 enhances CDKN1A stability and inhibits cell proliferation. Phosphorylation of Thr-145 by PIM1 results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. UV radiation-induced phosphorylation at Thr-80 by LKB1 and at Ser-146 by NUAK1 leads to its degradation"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15226418"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23213251"}],"value":"Ubiquitinated by MKRN1; leading to polyubiquitination and 26S proteasome-dependent degradation. Ubiquitinated by the DCX(DTL) complex, also named CRL4(CDT2) complex, leading to its degradation during S phase or following UV irradiation. 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