ID:CDN1A_HUMAN DESCRIPTION: RecName: Full=Cyclin-dependent kinase inhibitor 1; AltName: Full=CDK-interacting protein 1; AltName: Full=Melanoma differentiation-associated protein 6; Short=MDA-6; AltName: Full=p21; FUNCTION: May 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. SUBUNIT: 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. 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. INTERACTION: P78396:CCNA1; NbExp=2; IntAct=EBI-375077, EBI-375065; P20248:CCNA2; NbExp=2; IntAct=EBI-375077, EBI-457097; P24385:CCND1; NbExp=5; IntAct=EBI-375077, EBI-375001; P30281:CCND3; NbExp=3; IntAct=EBI-375077, EBI-375013; P24864:CCNE1; NbExp=7; IntAct=EBI-375077, EBI-519526; O96020:CCNE2; NbExp=2; IntAct=EBI-375077, EBI-375033; O94921:CDK14; NbExp=7; IntAct=EBI-375077, EBI-1043945; P24941:CDK2; NbExp=9; IntAct=EBI-375077, EBI-375096; P11802:CDK4; NbExp=4; IntAct=EBI-375077, EBI-295644; Q00535:CDK5; NbExp=2; IntAct=EBI-375077, EBI-1041567; Q9BQ15:NABP2; NbExp=7; IntAct=EBI-375077, EBI-2120336; P12004:PCNA; NbExp=4; IntAct=EBI-375077, EBI-358311; Q96FS4:SIPA1; NbExp=2; IntAct=EBI-375077, EBI-1054981; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. TISSUE SPECIFICITY: Expressed in all adult tissues, with 5-fold lower levels observed in the brain. INDUCTION: Activated by p53/TP53, mezerein (antileukemic compound) and IFNB1. Repressed by HDAC1. DOMAIN: The 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. DOMAIN: The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex. PTM: 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. PTM: 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. 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. PTM: Acetylation 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). SIMILARITY: Belongs to the CDI family. SEQUENCE CAUTION: Sequence=AAB59559.1; Type=Erroneous initiation; Note=Translation N-terminally shortened; Sequence=AAB59560.1; Type=Erroneous initiation; Note=Translation N-terminally shortened; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/CDKN1AID139.html"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/cdkn1a/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P38936
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0004693 cyclin-dependent protein serine/threonine kinase activity GO:0004860 protein kinase inhibitor activity GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity GO:0005515 protein binding GO:0019901 protein kinase binding GO:0019912 cyclin-dependent protein kinase activating kinase activity GO:0030332 cyclin binding GO:0031625 ubiquitin protein ligase binding GO:0044877 macromolecular complex binding GO:0046872 metal ion binding
Biological Process: GO:0000079 regulation of cyclin-dependent protein serine/threonine kinase activity GO:0000082 G1/S transition of mitotic cell cycle GO:0000086 G2/M transition of mitotic cell cycle GO:0006357 regulation of transcription from RNA polymerase II promoter GO:0006367 transcription initiation from RNA polymerase II promoter GO:0006974 cellular response to DNA damage stimulus GO:0006977 DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest GO:0006978 DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator GO:0007049 cell cycle GO:0007050 cell cycle arrest GO:0007265 Ras protein signal transduction GO:0007346 regulation of mitotic cell cycle GO:0008285 negative regulation of cell proliferation GO:0009411 response to UV GO:0009636 response to toxic substance GO:0010033 response to organic substance GO:0010165 response to X-ray GO:0010243 response to organonitrogen compound GO:0010629 negative regulation of gene expression GO:0010942 positive regulation of cell death GO:0014070 response to organic cyclic compound GO:0019221 cytokine-mediated signaling pathway GO:0030308 negative regulation of cell growth GO:0030890 positive regulation of B cell proliferation GO:0031100 animal organ regeneration GO:0031668 cellular response to extracellular stimulus GO:0033158 regulation of protein import into nucleus, translocation GO:0034198 cellular response to amino acid starvation GO:0034605 cellular response to heat GO:0042326 negative regulation of phosphorylation GO:0042493 response to drug GO:0042771 intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator GO:0043066 negative regulation of apoptotic process GO:0043068 positive regulation of programmed cell death GO:0045736 negative regulation of cyclin-dependent protein serine/threonine kinase activity GO:0045860 positive regulation of protein kinase activity GO:0046685 response to arsenic-containing substance GO:0048146 positive regulation of fibroblast proliferation GO:0050821 protein stabilization GO:0051384 response to glucocorticoid GO:0051412 response to corticosterone GO:0051726 regulation of cell cycle GO:0055093 response to hyperoxia GO:0060574 intestinal epithelial cell maturation GO:0071479 cellular response to ionizing radiation GO:0071480 cellular response to gamma radiation GO:0071493 cellular response to UV-B GO:0071850 mitotic cell cycle arrest GO:0072331 signal transduction by p53 class mediator GO:0090398 cellular senescence GO:0090399 replicative senescence GO:0090400 stress-induced premature senescence GO:0097193 intrinsic apoptotic signaling pathway GO:1904030 negative regulation of cyclin-dependent protein kinase activity GO:1904031 positive regulation of cyclin-dependent protein kinase activity GO:1904706 negative regulation of vascular smooth muscle cell proliferation GO:2000134 negative regulation of G1/S transition of mitotic cell cycle GO:2000278 regulation of DNA biosynthetic process GO:2000379 positive regulation of reactive oxygen species metabolic process
AK298901 - Homo sapiens cDNA FLJ54803 complete cds, highly similar to Cyclin-dependent kinase inhibitor 1. LF212702 - JP 2014500723-A/20205: Polycomb-Associated Non-Coding RNAs. AK309512 - Homo sapiens cDNA, FLJ99553. U09579 - Human melanoma differentiation associated (mda-6) mRNA, complete cds. BC013967 - Homo sapiens cyclin-dependent kinase inhibitor 1A (p21, Cip1), mRNA (cDNA clone MGC:8559 IMAGE:2822909), complete cds. AB209881 - Homo sapiens mRNA for Cyclin-dependent kinase variant protein. BC001935 - Homo sapiens cyclin-dependent kinase inhibitor 1A (p21, Cip1), mRNA (cDNA clone MGC:4059 IMAGE:2823668), complete cds. BC000312 - Homo sapiens cyclin-dependent kinase inhibitor 1A (p21, Cip1), mRNA (cDNA clone MGC:8428 IMAGE:2821049), complete cds. L25610 - Homo sapiens cyclin-dependent kinase inhibitor mRNA, complete cds. L26165 - Human DNA synthesis inhibitor mRNA, complete cds. U03106 - Human wild-type p53 activated fragment-1 (WAF1) mRNA, complete cds. S67388 - p21=cyclin kinase inhibitor [human, lung, WI38, mRNA, 600 nt]. BC000275 - Homo sapiens cyclin-dependent kinase inhibitor 1A (p21, Cip1), mRNA (cDNA clone MGC:3175 IMAGE:3355833), complete cds. L47232 - Homo sapiens cyclin-dependent kinase (CIP1/WAF1) mRNA, with a mutation (Ser 31 to Arg) predisposing to cancer, 3' end. L47233 - Homo sapiens cyclin-dependent kinase (CIP1/WAF1) mRNA, 3' end, with a cancer predisposing mutation in the 3' UTR. AY008263 - Homo sapiens cyclin-dependent kinase inhibitor isoform mRNA, complete cds. AB385124 - Synthetic construct DNA, clone: pF1KB5576, Homo sapiens CDKN1A gene for cyclin-dependent kinase inhibitor 1, complete cds, without stop codon, in Flexi system. AM392711 - Synthetic construct Homo sapiens clone IMAGE:100002746 for hypothetical protein (CDKN1A gene). AM392920 - Synthetic construct Homo sapiens clone IMAGE:100002996 for hypothetical protein (CDKN1A gene). KJ905711 - Synthetic construct Homo sapiens clone ccsbBroadEn_15381 CDKN1A gene, encodes complete protein. KJ890888 - Synthetic construct Homo sapiens clone ccsbBroadEn_00282 CDKN1A gene, encodes complete protein. KR709732 - Synthetic construct Homo sapiens clone CCSBHm_00005563 CDKN1A (CDKN1A) mRNA, encodes complete protein. KR709733 - Synthetic construct Homo sapiens clone CCSBHm_00005564 CDKN1A (CDKN1A) mRNA, encodes complete protein. KR709734 - Synthetic construct Homo sapiens clone CCSBHm_00005565 CDKN1A (CDKN1A) mRNA, encodes complete protein. KR709735 - Synthetic construct Homo sapiens clone CCSBHm_00005566 CDKN1A (CDKN1A) mRNA, encodes complete protein. AB451422 - Homo sapiens CDKN1A mRNA for cyclin-dependent kinase inhibitor 1A, partial cds, clone: FLJ08131AAAF. BT006719 - Homo sapiens cyclin-dependent kinase inhibitor 1A (p21, Cip1) mRNA, complete cds. AB451290 - Homo sapiens CDKN1A mRNA for cyclin-dependent kinase inhibitor 1A, complete cds, clone: FLJ08131AAAN. CR536533 - Homo sapiens full open reading frame cDNA clone RZPDo834A0522D for gene CDKN1A, cyclin-dependent kinase inhibitor 1A (p21, Cip1); complete cds, incl. stopcodon. BC037414 - Homo sapiens cDNA clone IMAGE:4523867, **** WARNING: chimeric clone ****. JD267732 - Sequence 248756 from Patent EP1572962. JD510376 - Sequence 491400 from Patent EP1572962. JD468828 - Sequence 449852 from Patent EP1572962. JD191936 - Sequence 172960 from Patent EP1572962. JD465077 - Sequence 446101 from Patent EP1572962. JD417495 - Sequence 398519 from Patent EP1572962. JD422960 - Sequence 403984 from Patent EP1572962. JD303212 - Sequence 284236 from Patent EP1572962. JD111546 - Sequence 92570 from Patent EP1572962. JD206003 - Sequence 187027 from Patent EP1572962. JD378049 - Sequence 359073 from Patent EP1572962. JD269873 - Sequence 250897 from Patent EP1572962. JD150362 - Sequence 131386 from Patent EP1572962. JD039950 - Sequence 20974 from Patent EP1572962. JD417429 - Sequence 398453 from Patent EP1572962. JD317529 - Sequence 298553 from Patent EP1572962. JD495061 - Sequence 476085 from Patent EP1572962. JD540498 - Sequence 521522 from Patent EP1572962. JD328981 - Sequence 310005 from Patent EP1572962. JD399608 - Sequence 380632 from Patent EP1572962. JD190730 - Sequence 171754 from Patent EP1572962. JD218139 - Sequence 199163 from Patent EP1572962. JD465409 - Sequence 446433 from Patent EP1572962. JD390744 - Sequence 371768 from Patent EP1572962. JD133128 - Sequence 114152 from Patent EP1572962. JD133129 - Sequence 114153 from Patent EP1572962. JD467074 - Sequence 448098 from Patent EP1572962. JD467075 - Sequence 448099 from Patent EP1572962. JD547265 - Sequence 528289 from Patent EP1572962. JD226666 - Sequence 207690 from Patent EP1572962. JD132466 - Sequence 113490 from Patent EP1572962. JD544656 - Sequence 525680 from Patent EP1572962. JD509892 - Sequence 490916 from Patent EP1572962. JD288647 - Sequence 269671 from Patent EP1572962. JD491405 - Sequence 472429 from Patent EP1572962. JD040389 - Sequence 21413 from Patent EP1572962. JD445656 - Sequence 426680 from Patent EP1572962. JD114677 - Sequence 95701 from Patent EP1572962. JD068823 - Sequence 49847 from Patent EP1572962. MA448279 - JP 2018138019-A/20205: Polycomb-Associated Non-Coding RNAs. MP067503 - Sequence 7 from Patent WO2018232288.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_RacCycDPathway - Influence of Ras and Rho proteins on G1 to S Transition h_g1Pathway - Cell Cycle: G1/S Check Point h_p53Pathway - p53 Signaling Pathway h_eponfkbPathway - Erythropoietin mediated neuroprotection through NF-kB h_p53hypoxiaPathway - Hypoxia and p53 in the Cardiovascular system h_atmPathway - ATM Signaling Pathway h_calcineurinPathway - Effects of calcineurin in Keratinocyte Differentiation h_g2Pathway - Cell Cycle: G2/M Checkpoint h_cellcyclePathway - Cyclins and Cell Cycle Regulation
Reactome (by CSHL, EBI, and GO)
Protein P38936 (Reactome details) participates in the following event(s):
R-HSA-187828 Translocation of p21 to the nucleus R-HSA-8852362 GTSE1 binds CDKN1A R-HSA-198613 AKT phosphorylates p21Cip1 and p27Kip1 R-HSA-2399969 AKT1 E17K mutant phosphorylates p21Cip1 and p27Kip1 R-HSA-8941915 Cip/Kip CDK inhibitors bind CDK4/6:CCND complexes R-HSA-69562 Inactivation of Cyclin E:Cdk2 complexes by p27/p21 R-HSA-187934 Inactivation of Cyclin A:Cdk2 complexes by p27/p21 R-HSA-8942607 Tyrosine kinases phosphorylate Cip/Kip inhibitors bound to CDK4/6:CCND complexes R-HSA-187520 Cyclin E/A:Cdk2-mediated phosphorylation of p27/p21 R-HSA-187916 Cyclin A:Cdk2 mediated phosphorylation of p27/p21 R-HSA-187552 Binding of phospho-p27/p21:Cdk2:Cyclin E/A to the SCF(Skp2):Cks1 complex R-HSA-8942836 CDK4/6:CCND complexes are activated by T-loop phosphorylation of CDK4/6 R-HSA-187575 Ubiquitination of phospho-p27/p21 R-HSA-69227 Cyclin D:CDK4/6 phosphorylates RB1 and prevents RB1 binding to E2F1/2/3:DP1/2 complexes R-HSA-1226094 Cyclin D:Cdk4/6 mediated phosphorylation of p130 (RBL2) and dissociation of phosphorylated p130 (RBL2) from DP1:E2F4/5 complex R-HSA-1226095 Cyclin D:CDK4/6 mediated phosphorylation of p107 (RBL1) and dissociation of phosphorylated p107 (p-RBL1) from DP1:E2F4 complex R-HSA-69202 Cyclin E associated events during G1/S transition R-HSA-69656 Cyclin A:Cdk2-associated events at S phase entry R-HSA-8852276 The role of GTSE1 in G2/M progression after G2 checkpoint R-HSA-2559586 DNA Damage/Telomere Stress Induced Senescence R-HSA-69895 Transcriptional activation of cell cycle inhibitor p21 R-HSA-6804116 TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest R-HSA-8866911 TFAP2 (AP-2) family regulates transcription of cell cycle factors R-HSA-8941855 RUNX3 regulates CDKN1A transcription R-HSA-8878166 Transcriptional regulation by RUNX2 R-HSA-198323 AKT phosphorylates targets in the cytosol R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer R-HSA-6785807 Interleukin-4 and 13 signaling R-HSA-69231 Cyclin D associated events in G1 R-HSA-69206 G1/S Transition R-HSA-69242 S Phase R-HSA-69275 G2/M Transition R-HSA-69563 p53-Dependent G1 DNA Damage Response R-HSA-2559583 Cellular Senescence R-HSA-69560 Transcriptional activation of p53 responsive genes R-HSA-6791312 TP53 Regulates Transcription of Cell Cycle Genes R-HSA-8864260 Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors R-HSA-8878159 Transcriptional regulation by RUNX3 R-HSA-212436 Generic Transcription Pathway R-HSA-1257604 PIP3 activates AKT signaling R-HSA-2219528 PI3K/AKT Signaling in Cancer R-HSA-449147 Signaling by Interleukins R-HSA-69236 G1 Phase R-HSA-453279 Mitotic G1-G1/S phases R-HSA-69278 Cell Cycle (Mitotic) R-HSA-453274 Mitotic G2-G2/M phases R-HSA-187577 SCF(Skp2)-mediated degradation of p27/p21 R-HSA-69580 p53-Dependent G1/S DNA damage checkpoint R-HSA-2262752 Cellular responses to stress R-HSA-3700989 Transcriptional Regulation by TP53 R-HSA-73857 RNA Polymerase II Transcription R-HSA-9006925 Intracellular signaling by second messengers R-HSA-5663202 Diseases of signal transduction R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-1640170 Cell Cycle R-HSA-69615 G1/S DNA Damage Checkpoints R-HSA-8953897 Cellular responses to external stimuli R-HSA-74160 Gene expression (Transcription) R-HSA-162582 Signal Transduction R-HSA-1643685 Disease R-HSA-168256 Immune System R-HSA-69620 Cell Cycle Checkpoints
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
