CDN1A_MOUSE
ID CDN1A_MOUSE Reviewed; 159 AA.
AC P39689;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 4.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=Cyclin-dependent kinase inhibitor 1;
DE AltName: Full=CDK-interacting protein 1;
DE AltName: Full=Melanoma differentiation-associated protein;
DE AltName: Full=p21;
GN Name=Cdkn1a; Synonyms=Cip1, Waf1;
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 [MRNA].
RC STRAIN=BXSB; TISSUE=Spleen;
RX PubMed=8084607;
RA Huppi K., Siwarski D., Dosik J., Michieli P., Chedid M., Reed S., Mock B.,
RA Givol D., Mushinski J.F.;
RT "Molecular cloning, sequencing, chromosomal localization and expression of
RT mouse p21 (Waf1).";
RL Oncogene 9:3017-3020(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7796420;
RA El-Deiry W.S., Tokino T., Waldman T., Velculescu V.E., Oliner J.D.,
RA Burell M., Hill D.E., Rees J.L., Hamilton S.R., Kinzler K.W.,
RA Vogelstein B.;
RT "Topological control of p21WAF1/CIP1 expression in normal and neoplastic
RT tissues.";
RL Cancer Res. 55:2910-2919(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Mammary gland;
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 [MRNA] OF 1-143.
RX PubMed=8242752; DOI=10.1016/0092-8674(93)90500-p;
RA El-Deiry W.S., Tokino T., Velculescu V.E., Levy D.B., Parsons R.,
RA Trent J.M., Lin D., Mercer W.E., Kinzler K.W., Vogelstein B.;
RT "WAF1, a potential mediator of p53 tumor suppression.";
RL Cell 75:817-825(1993).
RN [5]
RP INTERACTION WITH HDAC1, SUBCELLULAR LOCATION, AND ACETYLATION.
RX PubMed=20154723; DOI=10.1038/onc.2010.19;
RA Li Z., Zhang Q., Mao J.H., Weise A., Mrasek K., Fan X., Zhang X., Liehr T.,
RA Lu K.H., Balmain A., Cai W.W.;
RT "An HDAC1-binding domain within FATS bridges p21 turnover to radiation-
RT induced tumorigenesis.";
RL Oncogene 29:2659-2671(2010).
RN [6]
RP FUNCTION, INTERACTION WITH STK11, AND PHOSPHORYLATION AT SER-78 AND
RP SER-141.
RX PubMed=25329316; DOI=10.1371/journal.pgen.1004721;
RA Esteve-Puig R., Gil R., Gonzalez-Sanchez E., Bech-Serra J.J., Grueso J.,
RA Hernandez-Losa J., Moline T., Canals F., Ferrer B., Cortes J., Bastian B.,
RA Cajal S.R.Y., Martin-Caballero J., Flores J.M., Vivancos A.,
RA Garcia-Patos V., Recio J.A.;
RT "A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating
RT CDKN1A (p21WAF1/CIP1) degradation.";
RL PLoS Genet. 10:E1004721-E1004721(2014).
CC -!- FUNCTION: May be involved in p53/TP53 mediated inhibition of cellular
CC proliferation in response to DNA damage. Binds to and inhibits cyclin-
CC dependent kinase activity, preventing phosphorylation of critical
CC cyclin-dependent kinase substrates and blocking cell cycle progression.
CC Functions in the nuclear localization and assembly of cyclin D-CDK4
CC complex and promotes its kinase activity towards RB1. At higher
CC stoichiometric ratios, inhibits the kinase activity of the cyclin D-
CC CDK4 complex (PubMed:25329316). Inhibits DNA synthesis by DNA
CC polymerase delta by competing with POLD3 for PCNA binding (By
CC similarity). Plays an important role in controlling cell cycle
CC progression and DNA damage-induced G2 arrest (By similarity).
CC {ECO:0000250|UniProtKB:P38936, ECO:0000269|PubMed:25329316}.
CC -!- SUBUNIT: Interacts with HDAC1; the interaction is prevented by
CC competitive binding of C10orf90/FATS to HDAC1 facilitating acetylation
CC and protein stabilization of CDKN1A/p21 (PubMed:20154723). Interacts
CC with MKRN1. Interacts with PSMA3. Interacts with PCNA. Component of the
CC ternary complex, cyclin D-CDK4-CDKN1A. Interacts (via its N-terminal
CC domain) with CDK4; the interaction promotes the assembly of the cyclin
CC D-CDK4 complex, its nuclear translocation and promotes the cyclin D-
CC dependent enzyme activity of CDK4. Binding to CDK2 leads to CDK2/cyclin
CC E inactivation at the G1-S phase DNA damage checkpoint, thereby
CC arresting cells at the G1-S transition during DNA repair. Interacts
CC with PIM1 (By similarity). Interacts with STK11 (PubMed:25329316).
CC Interacts with NUAK1 (By similarity). Interacts with DTL and TRIM39 (By
CC similarity). {ECO:0000250|UniProtKB:P38936,
CC ECO:0000269|PubMed:20154723, ECO:0000269|PubMed:25329316}.
CC -!- INTERACTION:
CC P39689; Q9Z111: Gadd45g; NbExp=2; IntAct=EBI-1174103, EBI-1173616;
CC P39689; P17918: Pcna; NbExp=2; IntAct=EBI-1174103, EBI-1173716;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P38936}. Nucleus
CC {ECO:0000269|PubMed:20154723}.
CC -!- INDUCTION: By p53, mezerein (antileukemic compound) and interferon
CC beta.
CC -!- DOMAIN: The C-terminal is required for nuclear localization of the
CC cyclin D-CDK4 complex. {ECO:0000250}.
CC -!- DOMAIN: The PIP-box K+4 motif mediates both the interaction with PCNA
CC and the recruitment of the DCX(DTL) complex: while the PIP-box
CC interacts with PCNA, the presence of the K+4 submotif, recruits the
CC DCX(DTL) complex, leading to its ubiquitination. {ECO:0000250}.
CC -!- PTM: Phosphorylation of Thr-140 or Ser-141 impairs binding to PCNA.
CC Phosphorylation at Ser-112 by GSK3-beta enhances ubiquitination by the
CC DCX(DTL) complex (By similarity). Phosphorylation of Thr-140 by PIM2
CC enhances its stability and inhibits cell proliferation. Phosphorylation
CC of Thr-140 by PIM1 results in the relocation of CDKN1A to the cytoplasm
CC and enhanced CDKN1A protein stability. UV radiation-induced
CC phosphorylation at Ser-78 and Ser-141 by NUAK1 leads to its
CC degradation. {ECO:0000250|UniProtKB:P38936,
CC ECO:0000269|PubMed:25329316}.
CC -!- PTM: Ubiquitinated by MKRN1; leading to polyubiquitination and 26S
CC proteasome-dependent degradation. Ubiquitinated by the DCX(DTL)
CC complex, also named CRL4(CDT2) complex, leading to its degradation
CC during S phase or following UV irradiation. Ubiquitination by the
CC DCX(DTL) complex is essential to control replication licensing and is
CC PCNA-dependent: interacts with PCNA via its PIP-box, while the presence
CC of the containing the 'K+4' motif in the PIP box, recruit the DCX(DTL)
CC complex, leading to its degradation. Ubiquitination at Ser-2 leads to
CC degradation by the proteasome pathway. Ubiquitinated by RNF114; leading
CC to proteasomal degradation (By similarity).
CC {ECO:0000250|UniProtKB:P38936}.
CC -!- PTM: Acetylation leads to protein stability. Acetylated in vitro on
CC Lys-136, Lys-149, Lys-156 and Lys-158. Deacetylation by HDAC1 is
CC prevented by competitive binding of C10orf90/FATS to HDAC1.
CC {ECO:0000269|PubMed:20154723}.
CC -!- SIMILARITY: Belongs to the CDI family. {ECO:0000305}.
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DR EMBL; U09507; AAB60456.1; -; mRNA.
DR EMBL; U24173; AAC52220.1; -; mRNA.
DR EMBL; BC002043; AAH02043.1; -; mRNA.
DR CCDS; CCDS28591.1; -.
DR PIR; A49438; A49438.
DR PIR; I49023; I49023.
DR RefSeq; NP_001104569.1; NM_001111099.2.
DR RefSeq; NP_031695.1; NM_007669.5.
DR AlphaFoldDB; P39689; -.
DR SMR; P39689; -.
DR BioGRID; 198651; 15.
DR CORUM; P39689; -.
DR DIP; DIP-24178N; -.
DR ELM; P39689; -.
DR IntAct; P39689; 4.
DR MINT; P39689; -.
DR STRING; 10090.ENSMUSP00000023829; -.
DR iPTMnet; P39689; -.
DR PhosphoSitePlus; P39689; -.
DR EPD; P39689; -.
DR PaxDb; P39689; -.
DR PeptideAtlas; P39689; -.
DR PRIDE; P39689; -.
DR ProteomicsDB; 281569; -.
DR Antibodypedia; 3757; 2453 antibodies from 47 providers.
DR DNASU; 12575; -.
DR Ensembl; ENSMUST00000023829; ENSMUSP00000023829; ENSMUSG00000023067.
DR Ensembl; ENSMUST00000119901; ENSMUSP00000113150; ENSMUSG00000023067.
DR Ensembl; ENSMUST00000122348; ENSMUSP00000112411; ENSMUSG00000023067.
DR Ensembl; ENSMUST00000233296; ENSMUSP00000156559; ENSMUSG00000023067.
DR GeneID; 12575; -.
DR KEGG; mmu:12575; -.
DR UCSC; uc008bsg.2; mouse.
DR CTD; 1026; -.
DR MGI; MGI:104556; Cdkn1a.
DR VEuPathDB; HostDB:ENSMUSG00000023067; -.
DR eggNOG; KOG4743; Eukaryota.
DR GeneTree; ENSGT00940000159918; -.
DR HOGENOM; CLU_077692_1_1_1; -.
DR InParanoid; P39689; -.
DR OMA; KVCRRLF; -.
DR OrthoDB; 1595421at2759; -.
DR PhylomeDB; P39689; -.
DR TreeFam; TF101038; -.
DR Reactome; R-MMU-187577; SCF(Skp2)-mediated degradation of p27/p21.
DR Reactome; R-MMU-198323; AKT phosphorylates targets in the cytosol.
DR Reactome; R-MMU-2559582; Senescence-Associated Secretory Phenotype (SASP).
DR Reactome; R-MMU-2559586; DNA Damage/Telomere Stress Induced Senescence.
DR Reactome; R-MMU-6804116; TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest.
DR Reactome; R-MMU-69202; Cyclin E associated events during G1/S transition.
DR Reactome; R-MMU-69231; Cyclin D associated events in G1.
DR Reactome; R-MMU-69563; p53-Dependent G1 DNA Damage Response.
DR Reactome; R-MMU-69656; Cyclin A:Cdk2-associated events at S phase entry.
DR Reactome; R-MMU-8852276; The role of GTSE1 in G2/M progression after G2 checkpoint.
DR Reactome; R-MMU-9616222; Transcriptional regulation of granulopoiesis.
DR BioGRID-ORCS; 12575; 9 hits in 78 CRISPR screens.
DR ChiTaRS; Cdkn1a; mouse.
DR PRO; PR:P39689; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; P39689; protein.
DR Bgee; ENSMUSG00000023067; Expressed in stroma of bone marrow and 259 other tissues.
DR ExpressionAtlas; P39689; baseline and differential.
DR Genevisible; P39689; MM.
DR GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IPI:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0016604; C:nuclear body; ISO:MGI.
DR GO; GO:0005730; C:nucleolus; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0070557; C:PCNA-p21 complex; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0030332; F:cyclin binding; IDA:BHF-UCL.
DR GO; GO:0019912; F:cyclin-dependent protein kinase activating kinase activity; ISO:MGI.
DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; IDA:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0004860; F:protein kinase inhibitor activity; ISO:MGI.
DR GO; GO:0140311; F:protein sequestering activity; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0034198; P:cellular response to amino acid starvation; IMP:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IMP:MGI.
DR GO; GO:0031668; P:cellular response to extracellular stimulus; ISO:MGI.
DR GO; GO:0071480; P:cellular response to gamma radiation; IDA:MGI.
DR GO; GO:0071479; P:cellular response to ionizing radiation; ISO:MGI.
DR GO; GO:0071493; P:cellular response to UV-B; IDA:UniProtKB.
DR GO; GO:0090398; P:cellular senescence; ISO:MGI.
DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; ISO:MGI.
DR GO; GO:0006978; P:DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator; IDA:MGI.
DR GO; GO:0007507; P:heart development; IMP:BHF-UCL.
DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IMP:MGI.
DR GO; GO:0007095; P:mitotic G2 DNA damage checkpoint signaling; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:MGI.
DR GO; GO:1905179; P:negative regulation of cardiac muscle tissue regeneration; IMP:BHF-UCL.
DR GO; GO:0030308; P:negative regulation of cell growth; ISO:MGI.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:MGI.
DR GO; GO:1904030; P:negative regulation of cyclin-dependent protein kinase activity; ISO:MGI.
DR GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IDA:MGI.
DR GO; GO:2000279; P:negative regulation of DNA biosynthetic process; ISO:MGI.
DR GO; GO:2000134; P:negative regulation of G1/S transition of mitotic cell cycle; ISO:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:MGI.
DR GO; GO:0042326; P:negative regulation of phosphorylation; ISO:MGI.
DR GO; GO:0032091; P:negative regulation of protein binding; ISO:MGI.
DR GO; GO:1904706; P:negative regulation of vascular associated smooth muscle cell proliferation; ISO:MGI.
DR GO; GO:0030890; P:positive regulation of B cell proliferation; IGI:MGI.
DR GO; GO:0010942; P:positive regulation of cell death; ISO:MGI.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; ISO:MGI.
DR GO; GO:0043068; P:positive regulation of programmed cell death; IMP:MGI.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; ISO:MGI.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; ISO:MGI.
DR GO; GO:0006606; P:protein import into nucleus; IMP:MGI.
DR GO; GO:0007265; P:Ras protein signal transduction; IEA:Ensembl.
DR GO; GO:0051726; P:regulation of cell cycle; IDA:MGI.
DR GO; GO:1902806; P:regulation of cell cycle G1/S phase transition; ISS:UniProtKB.
DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; IMP:MGI.
DR GO; GO:2000278; P:regulation of DNA biosynthetic process; IMP:MGI.
DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; ISO:MGI.
DR GO; GO:0010389; P:regulation of G2/M transition of mitotic cell cycle; ISO:MGI.
DR GO; GO:0007346; P:regulation of mitotic cell cycle; IDA:MGI.
DR GO; GO:0009411; P:response to UV; IMP:MGI.
DR GO; GO:0042246; P:tissue regeneration; IMP:BHF-UCL.
DR GO; GO:0042060; P:wound healing; IMP:BHF-UCL.
DR Gene3D; 4.10.365.10; -; 1.
DR InterPro; IPR003175; CDI_dom.
DR InterPro; IPR044898; CDI_dom_sf.
DR InterPro; IPR029841; CDKN1A.
DR PANTHER; PTHR46778; PTHR46778; 1.
DR Pfam; PF02234; CDI; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cell cycle; Cytoplasm; Metal-binding; Nucleus; Phosphoprotein;
KW Protein kinase inhibitor; Reference proteome; Ubl conjugation; Zinc;
KW Zinc-finger.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P38936"
FT CHAIN 2..159
FT /note="Cyclin-dependent kinase inhibitor 1"
FT /id="PRO_0000190080"
FT ZN_FING 12..40
FT /note="C4-type"
FT /evidence="ECO:0000255"
FT REGION 17..24
FT /note="Required for binding cyclins"
FT /evidence="ECO:0000250"
FT REGION 53..58
FT /note="Required for binding CDKs"
FT /evidence="ECO:0000250"
FT REGION 78..106
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 118..142
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 147..159
FT /note="Interaction with TRIM39"
FT /evidence="ECO:0000250|UniProtKB:P38936"
FT MOTIF 135..159
FT /note="PIP-box K+4 motif"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:P38936"
FT MOD_RES 78
FT /note="Phosphoserine; by NUAK1"
FT /evidence="ECO:0000269|PubMed:25329316"
FT MOD_RES 112
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:P38936"
FT MOD_RES 125
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P38936"
FT MOD_RES 140
FT /note="Phosphothreonine; by PKA, PKB/AKT1, PIM1 and PIM2"
FT /evidence="ECO:0000250|UniProtKB:P38936"
FT MOD_RES 141
FT /note="Phosphoserine; by NUAK1"
FT /evidence="ECO:0000269|PubMed:25329316"
FT CROSSLNK 2
FT /note="Glycyl serine ester (Ser-Gly) (interchain with G-
FT Cter in ubiquitin)"
FT /evidence="ECO:0000250"
FT CONFLICT 30
FT /note="R -> S (in Ref. 4; no nucleotide entry)"
FT /evidence="ECO:0000305"
FT CONFLICT 56..57
FT /note="TP -> RQ (in Ref. 4; no nucleotide entry)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 159 AA; 17785 MW; 37B7C22B9A2FD089 CRC64;
MSNPGDVRPV PHRSKVCRCL FGPVDSEQLR RDCDALMAGC LQEARERWNF DFVTETPLEG
NFVWERVRSL GLPKVYLSPG SRSRDDLGGD KRPSTSSALL QGPAPEDHVA LSLSCTLVSE
RPEDSPGGPG TSQGRKRRQT SLTDFYHSKR RLVFCKRKP
