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Protein

Cyclin-dependent kinase inhibitor 1

Gene

Cdkn1a

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 (PubMed:25329316). Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (By similarity).By similarity1 Publication

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri12 – 40C4-typeSequence analysisAdd BLAST29

GO - Molecular functioni

GO - Biological processi

  • animal organ regeneration Source: Ensembl
  • cell cycle arrest Source: UniProtKB
  • cellular response to amino acid starvation Source: UniProtKB
  • cellular response to DNA damage stimulus Source: MGI
  • cellular response to extracellular stimulus Source: MGI
  • cellular response to gamma radiation Source: MGI
  • cellular response to heat Source: Ensembl
  • cellular response to ionizing radiation Source: MGI
  • cellular response to UV-B Source: UniProtKB
  • cellular senescence Source: MGI
  • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest Source: MGI
  • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator Source: MGI
  • G1/S transition of mitotic cell cycle Source: MGI
  • G2/M transition of mitotic cell cycle Source: MGI
  • intestinal epithelial cell maturation Source: Ensembl
  • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Source: MGI
  • mitotic cell cycle arrest Source: MGI
  • negative regulation of apoptotic process Source: Ensembl
  • negative regulation of cell growth Source: MGI
  • negative regulation of cell proliferation Source: MGI
  • negative regulation of cyclin-dependent protein serine/threonine kinase activity Source: MGI
  • negative regulation of G1/S transition of mitotic cell cycle Source: MGI
  • negative regulation of gene expression Source: MGI
  • negative regulation of phosphorylation Source: MGI
  • positive regulation of B cell proliferation Source: MGI
  • positive regulation of fibroblast proliferation Source: MGI
  • positive regulation of programmed cell death Source: MGI
  • positive regulation of protein kinase activity Source: MGI
  • positive regulation of reactive oxygen species metabolic process Source: MGI
  • Ras protein signal transduction Source: Ensembl
  • regulation of cell cycle Source: MGI
  • regulation of cyclin-dependent protein serine/threonine kinase activity Source: MGI
  • regulation of DNA biosynthetic process Source: MGI
  • regulation of mitotic cell cycle Source: MGI
  • regulation of protein import into nucleus, translocation Source: MGI
  • 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 UV Source: MGI
  • response to X-ray Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Protein kinase inhibitor

Keywords - Biological processi

Cell cycle

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-176408. Regulation of APC/C activators between G1/S and early anaphase.
R-MMU-187577. SCF(Skp2)-mediated degradation of p27/p21.
R-MMU-198323. AKT phosphorylates targets in the cytosol.
R-MMU-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-MMU-2559586. DNA Damage/Telomere Stress Induced Senescence.
R-MMU-6804116. TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest.
R-MMU-68949. Orc1 removal from chromatin.
R-MMU-69202. Cyclin E associated events during G1/S transition.
R-MMU-69231. Cyclin D associated events in G1.
R-MMU-69563. p53-Dependent G1 DNA Damage Response.
R-MMU-69656. Cyclin A:Cdk2-associated events at S phase entry.
R-MMU-8852276. The role of GTSE1 in G2/M progression after G2 checkpoint.

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase inhibitor 1
Alternative name(s):
CDK-interacting protein 1
Melanoma differentiation-associated protein
p21
Gene namesi
Name:Cdkn1a
Synonyms:Cip1, Waf1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 17

Organism-specific databases

MGIiMGI:104556. Cdkn1a.

Subcellular locationi

GO - Cellular componenti

  • cyclin-dependent protein kinase holoenzyme complex Source: MGI
  • cytoplasm Source: MGI
  • cytosol Source: MGI
  • nucleolus Source: MGI
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
  • PCNA-p21 complex Source: UniProtKB
  • perinuclear region of cytoplasm Source: Ensembl
  • protein complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00001900802 – 159Cyclin-dependent kinase inhibitor 1Add BLAST158

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Cross-linki2Glycyl serine ester (Ser-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei78Phosphoserine; by NUAK11 Publication1
Modified residuei112Phosphoserine; by GSK3-betaBy similarity1
Modified residuei125PhosphoserineBy similarity1
Modified residuei140Phosphothreonine; by PKA; PKB/AKT1; PIM1 and PIM2By similarity1
Modified residuei141Phosphoserine; by NUAK11 Publication1

Post-translational modificationi

Phosphorylation of Thr-140 or Ser-141 impairs binding to PCNA. Phosphorylation at Ser-112 by GSK3-beta enhances ubiquitination by the DCX(DTL) complex (By similarity). Phosphorylation of Thr-140 by PIM2 enhances its stability and inhibits cell proliferation. Phosphorylation of Thr-140 by PIM1 results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. UV radiation-induced phosphorylation at Ser-78 and Ser-141 by NUAK1 leads to its degradation.By similarity1 Publication
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 (By similarity).By similarity
Acetylation leads to protein stability. Acetylated in vitro on Lys-136, Lys-149, Lys-156 and Lys-158. Deacetylation by HDAC1 is prevented by competitive binding of C10orf90/FATS to HDAC1.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP39689.
PaxDbiP39689.
PeptideAtlasiP39689.
PRIDEiP39689.

PTM databases

iPTMnetiP39689.
PhosphoSitePlusiP39689.

Expressioni

Inductioni

By p53, mezerein (antileukemic compound) and interferon beta.

Gene expression databases

BgeeiENSMUSG00000023067.
CleanExiMM_CDKN1A.
ExpressionAtlasiP39689. baseline and differential.
GenevisibleiP39689. MM.

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 (PubMed:20154723). 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 (By similarity). Interacts with STK11 (PubMed:25329316). Interacts with NUAK1 (By similarity).By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Gadd45gQ9Z1112EBI-1174103,EBI-1173616

GO - Molecular functioni

  • cyclin binding Source: MGI
  • ubiquitin protein ligase binding Source: MGI

Protein-protein interaction databases

BioGridi198651. 15 interactors.
DIPiDIP-24178N.
IntActiP39689. 3 interactors.
MINTiMINT-1529153.
STRINGi10090.ENSMUSP00000023829.

Structurei

3D structure databases

ProteinModelPortaliP39689.
SMRiP39689.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni17 – 24Required for binding cyclinsBy similarity8
Regioni53 – 58Required for binding CDKsBy similarity6

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi135 – 159PIP-box K+4 motifAdd BLAST25

Domaini

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

Sequence similaritiesi

Belongs to the CDI family.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri12 – 40C4-typeSequence analysisAdd BLAST29

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4743. Eukaryota.
ENOG410XXN5. LUCA.
GeneTreeiENSGT00530000063588.
HOGENOMiHOG000285999.
HOVERGENiHBG050868.
InParanoidiP39689.
KOiK06625.
OMAiFAWERVW.
OrthoDBiEOG091G19PZ.
PhylomeDBiP39689.
TreeFamiTF101038.

Family and domain databases

InterProiIPR003175. CDI.
IPR029841. CDKN1A_vertebrate.
[Graphical view]
PANTHERiPTHR10265. PTHR10265. 1 hit.
PTHR10265:SF16. PTHR10265:SF16. 1 hit.
PfamiPF02234. CDI. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

P39689-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSNPGDVRPV PHRSKVCRCL FGPVDSEQLR RDCDALMAGC LQEARERWNF
60 70 80 90 100
DFVTETPLEG NFVWERVRSL GLPKVYLSPG SRSRDDLGGD KRPSTSSALL
110 120 130 140 150
QGPAPEDHVA LSLSCTLVSE RPEDSPGGPG TSQGRKRRQT SLTDFYHSKR

RLVFCKRKP
Length:159
Mass (Da):17,785
Last modified:January 23, 2007 - v4
Checksum:i37B7C22B9A2FD089
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti30R → S no nucleotide entry (PubMed:8242752).Curated1
Sequence conflicti56 – 57TP → RQ no nucleotide entry (PubMed:8242752).Curated2

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U09507 mRNA. Translation: AAB60456.1.
U24173 mRNA. Translation: AAC52220.1.
BC002043 mRNA. Translation: AAH02043.1.
CCDSiCCDS28591.1.
PIRiA49438.
I49023.
RefSeqiNP_001104569.1. NM_001111099.2.
NP_031695.1. NM_007669.5.
UniGeneiMm.195663.

Genome annotation databases

EnsembliENSMUST00000023829; ENSMUSP00000023829; ENSMUSG00000023067.
ENSMUST00000119901; ENSMUSP00000113150; ENSMUSG00000023067.
ENSMUST00000122348; ENSMUSP00000112411; ENSMUSG00000023067.
GeneIDi12575.
KEGGimmu:12575.
UCSCiuc008bsg.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U09507 mRNA. Translation: AAB60456.1.
U24173 mRNA. Translation: AAC52220.1.
BC002043 mRNA. Translation: AAH02043.1.
CCDSiCCDS28591.1.
PIRiA49438.
I49023.
RefSeqiNP_001104569.1. NM_001111099.2.
NP_031695.1. NM_007669.5.
UniGeneiMm.195663.

3D structure databases

ProteinModelPortaliP39689.
SMRiP39689.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198651. 15 interactors.
DIPiDIP-24178N.
IntActiP39689. 3 interactors.
MINTiMINT-1529153.
STRINGi10090.ENSMUSP00000023829.

PTM databases

iPTMnetiP39689.
PhosphoSitePlusiP39689.

Proteomic databases

EPDiP39689.
PaxDbiP39689.
PeptideAtlasiP39689.
PRIDEiP39689.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000023829; ENSMUSP00000023829; ENSMUSG00000023067.
ENSMUST00000119901; ENSMUSP00000113150; ENSMUSG00000023067.
ENSMUST00000122348; ENSMUSP00000112411; ENSMUSG00000023067.
GeneIDi12575.
KEGGimmu:12575.
UCSCiuc008bsg.2. mouse.

Organism-specific databases

CTDi1026.
MGIiMGI:104556. Cdkn1a.

Phylogenomic databases

eggNOGiKOG4743. Eukaryota.
ENOG410XXN5. LUCA.
GeneTreeiENSGT00530000063588.
HOGENOMiHOG000285999.
HOVERGENiHBG050868.
InParanoidiP39689.
KOiK06625.
OMAiFAWERVW.
OrthoDBiEOG091G19PZ.
PhylomeDBiP39689.
TreeFamiTF101038.

Enzyme and pathway databases

ReactomeiR-MMU-176408. Regulation of APC/C activators between G1/S and early anaphase.
R-MMU-187577. SCF(Skp2)-mediated degradation of p27/p21.
R-MMU-198323. AKT phosphorylates targets in the cytosol.
R-MMU-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-MMU-2559586. DNA Damage/Telomere Stress Induced Senescence.
R-MMU-6804116. TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest.
R-MMU-68949. Orc1 removal from chromatin.
R-MMU-69202. Cyclin E associated events during G1/S transition.
R-MMU-69231. Cyclin D associated events in G1.
R-MMU-69563. p53-Dependent G1 DNA Damage Response.
R-MMU-69656. Cyclin A:Cdk2-associated events at S phase entry.
R-MMU-8852276. The role of GTSE1 in G2/M progression after G2 checkpoint.

Miscellaneous databases

ChiTaRSiCdkn1a. mouse.
PROiP39689.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000023067.
CleanExiMM_CDKN1A.
ExpressionAtlasiP39689. baseline and differential.
GenevisibleiP39689. MM.

Family and domain databases

InterProiIPR003175. CDI.
IPR029841. CDKN1A_vertebrate.
[Graphical view]
PANTHERiPTHR10265. PTHR10265. 1 hit.
PTHR10265:SF16. PTHR10265:SF16. 1 hit.
PfamiPF02234. CDI. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCDN1A_MOUSE
AccessioniPrimary (citable) accession number: P39689
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: January 23, 2007
Last modified: November 30, 2016
This is version 147 of the entry and version 4 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.