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MGP000512

UniProt Annotations

Entry Information
Gene Namecyclin-dependent kinase inhibitor 1A (p21, Cip1)
Protein EntryCDN1A_HUMAN
UniProt IDP38936
SpeciesHuman
Comments
Comment typeDescription
DomainThe C-terminal is required for nuclear localization of the cyclin D-CDK4 complex.
DomainThe PIP-box K+4 motif mediates both the interaction with PCNA and the recuitment 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.
FunctionMay be the important intermediate by which p53/TP53 mediates its role as an inhibitor of cellular proliferation in response to DNA damage. 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. {ECO:0000269|PubMed:8242751, ECO:0000269|PubMed:9106657}.
InductionActivated by p53/TP53, mezerein (antileukemic compound) and IFNB1. Repressed by HDAC1. {ECO:0000269|PubMed:8242751, ECO:0000269|PubMed:8242752}.
InteractionP27958:- (xeno); NbExp=3; IntAct=EBI-375077, EBI-6377335; P78396:CCNA1; NbExp=3; IntAct=EBI-375077, EBI-375065; P20248:CCNA2; NbExp=2; IntAct=EBI-375077, EBI-457097; P24385:CCND1; NbExp=6; IntAct=EBI-375077, EBI-375001; P30279:CCND2; NbExp=3; IntAct=EBI-375077, EBI-748789; P30281:CCND3; NbExp=4; IntAct=EBI-375077, EBI-375013; P24864:CCNE1; NbExp=9; IntAct=EBI-375077, EBI-519526; O96020:CCNE2; NbExp=2; IntAct=EBI-375077, EBI-375033; O75419:CDC45; NbExp=2; IntAct=EBI-375077, EBI-374969; Q99741:CDC6; NbExp=2; IntAct=EBI-375077, EBI-374862; O94921:CDK14; NbExp=8; IntAct=EBI-375077, EBI-1043945; P24941:CDK2; NbExp=14; IntAct=EBI-375077, EBI-375096; P11802:CDK4; NbExp=5; IntAct=EBI-375077, EBI-295644; Q00535:CDK5; NbExp=4; IntAct=EBI-375077, EBI-1041567; Q9UHC7:MKRN1; NbExp=5; IntAct=EBI-375077, EBI-373524; Q9BQ15:NABP2; NbExp=7; IntAct=EBI-375077, EBI-2120336; P12004:PCNA; NbExp=6; IntAct=EBI-375077, EBI-358311; Q6FI35:PCNA; NbExp=2; IntAct=EBI-375077, EBI-8469539; Q96FS4:SIPA1; NbExp=2; IntAct=EBI-375077, EBI-1054981; P63208:SKP1; NbExp=3; IntAct=EBI-375077, EBI-307486; Q13309:SKP2; NbExp=2; IntAct=EBI-375077, EBI-456291; P04637:TP53; NbExp=3; IntAct=EBI-375077, EBI-366083;
PtmAcetylation leads to protein stability. Acetylated in vitro on Lys-141, Lys-154, Lys-161 and Lys-163. Deacetylation by HDAC1 is prevented by competitive binding of C10orf90/FATS to HDAC1 (By similarity). {ECO:0000250}.
PtmPhosphorylation 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. {ECO:0000269|PubMed:10753973, ECO:0000269|PubMed:11463845, ECO:0000269|PubMed:12431783, ECO:0000269|PubMed:16964243, ECO:0000269|PubMed:16982699, ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:18794347, ECO:0000269|PubMed:20307683}.
PtmUbiquitinated 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. Ubiquitination by the DCX(DTL) complex is essential to control replication licensing and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Ubiquitination at Ser-2 leads to degradation by the proteasome pathway. Ubiquitinated by RNF114; leading to proteasomal degradation. {ECO:0000269|PubMed:15226418}.
Sequence CautionSequence=AAB59559.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; Sequence=AAB59560.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
SimilarityBelongs to the CDI family. {ECO:0000305}.
Subcellular LocationCytoplasm. Nucleus.
SubunitInteracts 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. Interacts with PSMA3. Interacts with PCNA. 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. 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. Interacts with PIM1. {ECO:0000250, ECO:0000269|PubMed:11350925, ECO:0000269|PubMed:12431783, ECO:0000269|PubMed:18703516, ECO:0000269|PubMed:18794347, ECO:0000269|PubMed:19445729, ECO:0000269|PubMed:19536131, ECO:0000269|PubMed:8861913, ECO:0000269|PubMed:9106657}.
Tissue SpecificityExpressed in all adult tissues, with 5-fold lower levels observed in the brain.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/CDKN1AID139.html";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/cdkn1a/";
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