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Protein

Cyclin-dependent kinase inhibitor 1

Gene

CDKN1A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

May be involved in p53/TP53 mediated inhibition 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. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (PubMed:11595739).3 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri13 – 41C4-typeSequence analysisAdd BLAST29

GO - Molecular functioni

  • cyclin binding Source: Ensembl
  • cyclin-dependent protein kinase activating kinase activity Source: UniProtKB
  • cyclin-dependent protein serine/threonine kinase activity Source: Reactome
  • cyclin-dependent protein serine/threonine kinase inhibitor activity Source: BHF-UCL
  • metal ion binding Source: UniProtKB-KW
  • protein-containing complex binding Source: CAFA
  • protein kinase binding Source: CAFA
  • protein kinase inhibitor activity Source: CAFA
  • ubiquitin protein ligase binding Source: UniProtKB

GO - Biological processi

  • animal organ regeneration Source: Ensembl
  • cell cycle arrest Source: BHF-UCL
  • cellular response to amino acid starvation Source: UniProtKB
  • cellular response to DNA damage stimulus Source: BHF-UCL
  • cellular response to extracellular stimulus Source: BHF-UCL
  • cellular response to gamma radiation Source: Ensembl
  • cellular response to heat Source: Ensembl
  • cellular response to ionizing radiation Source: BHF-UCL
  • cellular response to UV-B Source: UniProtKB
  • cellular senescence Source: BHF-UCL
  • cytokine-mediated signaling pathway Source: Reactome
  • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest Source: BHF-UCL
  • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator Source: Ensembl
  • G1/S transition of mitotic cell cycle Source: BHF-UCL
  • G2/M transition of mitotic cell cycle Source: BHF-UCL
  • intestinal epithelial cell maturation Source: Ensembl
  • intrinsic apoptotic signaling pathway Source: ProtInc
  • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Source: Ensembl
  • mitotic cell cycle arrest Source: Ensembl
  • negative regulation of apoptotic process Source: Ensembl
  • negative regulation of cell growth Source: BHF-UCL
  • negative regulation of cell proliferation Source: BHF-UCL
  • negative regulation of cyclin-dependent protein kinase activity Source: CAFA
  • negative regulation of cyclin-dependent protein serine/threonine kinase activity Source: Ensembl
  • negative regulation of G1/S transition of mitotic cell cycle Source: MGI
  • negative regulation of gene expression Source: Ensembl
  • negative regulation of phosphorylation Source: BHF-UCL
  • negative regulation of vascular smooth muscle cell proliferation Source: BHF-UCL
  • positive regulation of B cell proliferation Source: Ensembl
  • positive regulation of fibroblast proliferation Source: BHF-UCL
  • positive regulation of programmed cell death Source: Ensembl
  • positive regulation of protein kinase activity Source: MGI
  • positive regulation of reactive oxygen species metabolic process Source: BHF-UCL
  • protein stabilization Source: Reactome
  • Ras protein signal transduction Source: BHF-UCL
  • regulation of cyclin-dependent protein serine/threonine kinase activity Source: ProtInc
  • regulation of DNA biosynthetic process Source: Ensembl
  • regulation of protein import into nucleus, translocation Source: Ensembl
  • regulation of transcription by RNA polymerase II Source: Reactome
  • replicative senescence Source: Ensembl
  • response to arsenic-containing substance Source: Ensembl
  • response to corticosterone Source: Ensembl
  • response to drug Source: Ensembl
  • response to hyperoxia Source: Ensembl
  • response to organonitrogen compound Source: Ensembl
  • response to toxic substance Source: Ensembl
  • response to X-ray Source: Ensembl
  • stress-induced premature senescence Source: BHF-UCL
  • transcription initiation from RNA polymerase II promoter Source: Reactome

Keywordsi

Molecular functionProtein kinase inhibitor
Biological processCell cycle
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-187577 SCF(Skp2)-mediated degradation of p27/p21
R-HSA-198323 AKT phosphorylates targets in the cytosol
R-HSA-2559582 Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559586 DNA Damage/Telomere Stress Induced Senescence
R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-6785807 Interleukin-4 and 13 signaling
R-HSA-6804116 TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest
R-HSA-69202 Cyclin E associated events during G1/S transition
R-HSA-69231 Cyclin D associated events in G1
R-HSA-69563 p53-Dependent G1 DNA Damage Response
R-HSA-69656 Cyclin A:Cdk2-associated events at S phase entry
R-HSA-69895 Transcriptional activation of cell cycle inhibitor p21
R-HSA-8852276 The role of GTSE1 in G2/M progression after G2 checkpoint
R-HSA-8866911 TFAP2 (AP-2) family regulates transcription of cell cycle factors
R-HSA-8878166 Transcriptional regulation by RUNX2
R-HSA-8941855 RUNX3 regulates CDKN1A transcription
SIGNORiP38936

Protein family/group databases

MoonDBiP38936 Predicted

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase inhibitor 1
Alternative name(s):
CDK-interacting protein 1
Melanoma differentiation-associated protein 6
Short name:
MDA-6
p21
Gene namesi
Name:CDKN1A
Synonyms:CAP20, CDKN1, CIP1, MDA6, PIC1, SDI1, WAF1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

EuPathDBiHostDB:ENSG00000124762.13
HGNCiHGNC:1784 CDKN1A
MIMi116899 gene
neXtProtiNX_P38936

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi80T → A: Abolishes UV radiation-induced phosphorylation and subsequent degradation. 1 Publication1
Mutagenesisi114S → E: Phosphomimetic mutant, increases ubiquitination by the DCX(DTL) complex. 1 Publication1
Mutagenesisi144 – 150QTSMTDF → ATSATDA: Abolishes interaction with PCNA and subsequent degradation by the proteasome. 1 Publication7
Mutagenesisi145T → A: Reduces phosphorylation by Akt; no change in interaction with PCNA, CDK2 or CDK4; no change in subcellular location. 1 Publication1
Mutagenesisi145T → D: No interaction with PCNA; 59% inhibition of CDK2 binding; modest inhibition of CDK4 binding; no change in subcellular location. 1 Publication1
Mutagenesisi146S → A: No change in interaction with PCNA. Abolishes UV radiation-induced phosphorylation and subsequent degradation. 2 Publications1
Mutagenesisi146S → D: Reduces interaction with PCNA. 1 Publication1
Mutagenesisi147 – 151MTDFY → ATDAAA: Abolishes interaction with PCNA and subsequent degradation by the proteasome. 1 Publication5
Mutagenesisi154 – 156KRR → AAA: Abolishes degradation by the proteasome without affecting the interaction with PCNA. 1 Publication3

Organism-specific databases

DisGeNETi1026
MalaCardsiCDKN1A
OpenTargetsiENSG00000124762
Orphaneti652 Multiple endocrine neoplasia type 1
PharmGKBiPA104

Chemistry databases

ChEMBLiCHEMBL5021

Polymorphism and mutation databases

BioMutaiCDKN1A
DMDMi729143

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved1 Publication
ChainiPRO_00001900792 – 164Cyclin-dependent kinase inhibitor 1Add BLAST163

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserine1 Publication1
Cross-linki2Glycyl serine ester (Ser-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei80Phosphothreonine; by LKB11 Publication1
Modified residuei114Phosphoserine; by GSK3-beta1 Publication1
Modified residuei130PhosphoserineCombined sources1
Modified residuei145Phosphothreonine; by PKA, PKB/AKT1, PIM1 and PIM25 Publications1
Modified residuei146Phosphoserine; by PKC and NUAK12 Publications1
Modified residuei160Phosphoserine; by PKC; in vitro1 Publication1

Post-translational modificationi

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.7 Publications
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. Ubiquitination at Ser-2 leads to degradation by the proteasome pathway. Ubiquitinated by RNF114; leading to proteasomal degradation.1 Publication
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).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP38936
PaxDbiP38936
PeptideAtlasiP38936
PRIDEiP38936
ProteomicsDBi55307

2D gel databases

SWISS-2DPAGEiP38936

PTM databases

iPTMnetiP38936
PhosphoSitePlusiP38936

Expressioni

Tissue specificityi

Expressed in all adult tissues, with 5-fold lower levels observed in the brain.

Inductioni

Activated by p53/TP53, mezerein (antileukemic compound) and IFNB1. Repressed by HDAC1.2 Publications

Gene expression databases

BgeeiENSG00000124762
CleanExiHS_CDKN1A
ExpressionAtlasiP38936 baseline and differential
GenevisibleiP38936 HS

Organism-specific databases

HPAiCAB000064
CAB069401
HPA005946

Interactioni

Subunit structurei

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:18794347, PubMed:18703516, 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).By similarity10 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • cyclin binding Source: Ensembl
  • protein kinase binding Source: CAFA
  • ubiquitin protein ligase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi107460, 276 interactors
CORUMiP38936
DIPiDIP-246N
IntActiP38936, 183 interactors
MINTiP38936
STRINGi9606.ENSP00000244741

Chemistry databases

BindingDBiP38936

Structurei

Secondary structure

1164
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi147 – 149Combined sources3
Beta strandi153 – 158Combined sources6

3D structure databases

DisProtiDP00016
ProteinModelPortaliP38936
SMRiP38936
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP38936

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni17 – 24Required for binding cyclins8
Regioni53 – 58Required for binding CDKs6

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi140 – 164PIP-box K+4 motifAdd BLAST25
Motifi141 – 156Nuclear localization signalSequence analysisAdd BLAST16

Domaini

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.
The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex.

Sequence similaritiesi

Belongs to the CDI family.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri13 – 41C4-typeSequence analysisAdd BLAST29

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4743 Eukaryota
ENOG410XXN5 LUCA
GeneTreeiENSGT00530000063588
HOGENOMiHOG000285999
HOVERGENiHBG050868
InParanoidiP38936
KOiK06625
OMAiFAWERVW
OrthoDBiEOG091G19PZ
PhylomeDBiP38936
TreeFamiTF101038

Family and domain databases

InterProiView protein in InterPro
IPR003175 CDI
IPR029841 CDKN1A_vertebrate
PANTHERiPTHR10265 PTHR10265, 1 hit
PTHR10265:SF16 PTHR10265:SF16, 1 hit
PfamiView protein in Pfam
PF02234 CDI, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P38936-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSEPAGDVRQ NPCGSKACRR LFGPVDSEQL SRDCDALMAG CIQEARERWN
60 70 80 90 100
FDFVTETPLE GDFAWERVRG LGLPKLYLPT GPRRGRDELG GGRRPGTSPA
110 120 130 140 150
LLQGTAEEDH VDLSLSCTLV PRSGEQAEGS PGGPGDSQGR KRRQTSMTDF
160
YHSKRRLIFS KRKP
Length:164
Mass (Da):18,119
Last modified:January 23, 2007 - v3
Checksum:i98D1E7C519ADFCA9
GO

Sequence cautioni

The sequence AAB59559 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence AAB59560 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0486864P → L. Corresponds to variant dbSNP:rs4986866Ensembl.1
Natural variantiVAR_01187031S → R3 PublicationsCorresponds to variant dbSNP:rs1801270EnsemblClinVar.1
Natural variantiVAR_04868763F → L. Corresponds to variant dbSNP:rs4986867Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L25610 mRNA Translation: AAA16109.1
S67388 mRNA Translation: AAB29246.1
U09579 mRNA Translation: AAA85641.1
U03106 mRNA Translation: AAC04313.1
L26165 mRNA Translation: AAA19811.1
L47232 mRNA Translation: AAB59559.1 Different initiation.
L47233 mRNA Translation: AAB59560.1 Different initiation.
AF497972 Genomic DNA Translation: AAM11787.1
BT006719 mRNA Translation: AAP35365.1
AB451290 mRNA Translation: BAG70104.1
AB451422 mRNA Translation: BAG70236.1
CR536533 mRNA Translation: CAG38770.1
Z85996 Genomic DNA No translation available.
CH471081 Genomic DNA Translation: EAX03904.1
BC000275 mRNA Translation: AAH00275.1
BC000312 mRNA Translation: AAH00312.1
BC001935 mRNA Translation: AAH01935.1
BC013967 mRNA Translation: AAH13967.1
CCDSiCCDS4824.1
PIRiI54380
I68674
RefSeqiNP_000380.1, NM_000389.4
NP_001207706.1, NM_001220777.1
NP_001207707.1, NM_001220778.1
NP_001278478.1, NM_001291549.1
NP_510867.1, NM_078467.2
UniGeneiHs.370771
Hs.732576

Genome annotation databases

EnsembliENST00000244741; ENSP00000244741; ENSG00000124762
ENST00000373711; ENSP00000362815; ENSG00000124762
ENST00000405375; ENSP00000384849; ENSG00000124762
ENST00000448526; ENSP00000409259; ENSG00000124762
ENST00000615513; ENSP00000482768; ENSG00000124762
GeneIDi1026
KEGGihsa:1026
UCSCiuc003omm.5 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCDN1A_HUMAN
AccessioniPrimary (citable) accession number: P38936
Secondary accession number(s): Q14010, Q6FI05, Q9BUT4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: January 23, 2007
Last modified: July 18, 2018
This is version 209 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 6
    Human chromosome 6: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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