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P39689 (CDN1A_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 123. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclin-dependent kinase inhibitor 1
Alternative name(s):
CDK-interacting protein 1
Melanoma differentiation-associated protein
p21
Gene names
Name:Cdkn1a
Synonyms:Cip1, Waf1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length159 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

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 By similarity.

Subunit structure

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 By similarity. Interacts with HDAC1; the interaction is prevented by competitive binding of C10orf90/FATS to HDAC1 facilitating acetylation and protein stabilization of CDKN1A/p21. Interacts with PIM1 By similarity. Ref.5

Subcellular location

Cytoplasm By similarity. Nucleus Ref.5.

Induction

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

Domain

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 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 By similarity.

Post-translational modification

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.

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.

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. Ref.5

Sequence similarities

Belongs to the CDI family.

Ontologies

Keywords
   Biological processCell cycle
   Cellular componentCytoplasm
Nucleus
   DomainZinc-finger
   LigandMetal-binding
Zinc
   Molecular functionProtein kinase inhibitor
   PTMAcetylation
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest

Inferred from electronic annotation. Source: Ensembl

G1/S transition of mitotic cell cycle

Inferred from electronic annotation. Source: Ensembl

G2/M transition of mitotic cell cycle

Inferred from electronic annotation. Source: Ensembl

Ras protein signal transduction

Inferred from electronic annotation. Source: Ensembl

cell cycle arrest

Inferred from direct assay PubMed 15831459. Source: MGI

cellular response to DNA damage stimulus

Inferred from mutant phenotype PubMed 12952892. Source: MGI

cellular response to extracellular stimulus

Inferred from electronic annotation. Source: Ensembl

cellular response to ionizing radiation

Inferred from electronic annotation. Source: Ensembl

cellular senescence

Inferred from electronic annotation. Source: Ensembl

intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator

Inferred from mutant phenotype PubMed 12952892. Source: MGI

mitotic cell cycle arrest

Inferred from direct assay PubMed 17515607. Source: MGI

negative regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell growth

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell proliferation

Inferred from mutant phenotype PubMed 12759355PubMed 14712235. Source: MGI

negative regulation of cyclin-dependent protein serine/threonine kinase activity

Inferred from direct assay PubMed 12130539. Source: MGI

negative regulation of gene expression

Inferred from mutant phenotype PubMed 11981756. Source: MGI

organ regeneration

Inferred from electronic annotation. Source: Ensembl

positive regulation of B cell proliferation

Inferred from genetic interaction PubMed 12970760. Source: MGI

positive regulation of fibroblast proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of programmed cell death

Inferred from mutant phenotype PubMed 12759355. Source: MGI

positive regulation of reactive oxygen species metabolic process

Inferred from electronic annotation. Source: Ensembl

regulation of DNA biosynthetic process

Inferred from mutant phenotype PubMed 11981756. Source: MGI

regulation of cell cycle

Inferred from direct assay PubMed 12588994. Source: MGI

regulation of cyclin-dependent protein serine/threonine kinase activity

Inferred from mutant phenotype PubMed 11981756. Source: MGI

regulation of mitotic cell cycle

Inferred from mutant phenotype PubMed 11981756. Source: MGI

regulation of protein import into nucleus, translocation

Inferred from mutant phenotype PubMed 11981756. Source: MGI

response to UV

Inferred from mutant phenotype PubMed 12952892. Source: MGI

response to arsenic-containing substance

Inferred from electronic annotation. Source: Ensembl

response to corticosterone

Inferred from electronic annotation. Source: Ensembl

response to drug

Inferred from electronic annotation. Source: Ensembl

response to gamma radiation

Inferred from electronic annotation. Source: Ensembl

response to hyperoxia

Inferred from electronic annotation. Source: Ensembl

response to organonitrogen compound

Inferred from electronic annotation. Source: Ensembl

response to toxic substance

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentPCNA-p21 complex

Inferred from sequence or structural similarity. Source: UniProtKB

cyclin-dependent protein kinase holoenzyme complex

Inferred from physical interaction PubMed 12970760. Source: MGI

cytoplasm

Inferred from direct assay PubMed 11254359. Source: MGI

cytosol

Inferred from direct assay PubMed 15964824. Source: MGI

nucleus

Inferred from direct assay PubMed 11254359PubMed 12970760. Source: MGI

   Molecular_functioncyclin binding

Inferred from direct assay PubMed 12124778. Source: MGI

cyclin-dependent protein kinase activating kinase activity

Inferred from electronic annotation. Source: Ensembl

cyclin-dependent protein serine/threonine kinase inhibitor activity

Inferred from direct assay PubMed 12130539. Source: MGI

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction PubMed 11022036. Source: IntAct

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Gadd45gQ9Z1112EBI-1174103,EBI-1173616

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 159158Cyclin-dependent kinase inhibitor 1
PRO_0000190080

Regions

Zinc finger12 – 4029C4-type Potential
Region17 – 248Required for binding cyclins By similarity
Region53 – 586Required for binding CDKs By similarity
Motif135 – 15925PIP-box K+4 motif

Amino acid modifications

Modified residue21N-acetylserine By similarity
Modified residue1121Phosphoserine; by GSK3-beta By similarity
Modified residue1251Phosphoserine By similarity
Modified residue1401Phosphothreonine; by PKA; PKB/AKT1; PIM1 and PIM2 By similarity
Modified residue1411Phosphoserine By similarity
Cross-link2Glycyl serine ester (Ser-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Sequence conflict301R → S no nucleotide entry Ref.4
Sequence conflict56 – 572TP → RQ no nucleotide entry Ref.4

Sequences

Sequence LengthMass (Da)Tools
P39689 [UniParc].

Last modified January 23, 2007. Version 4.
Checksum: 37B7C22B9A2FD089

FASTA15917,785
        10         20         30         40         50         60 
MSNPGDVRPV PHRSKVCRCL FGPVDSEQLR RDCDALMAGC LQEARERWNF DFVTETPLEG 

        70         80         90        100        110        120 
NFVWERVRSL GLPKVYLSPG SRSRDDLGGD KRPSTSSALL QGPAPEDHVA LSLSCTLVSE 

       130        140        150 
RPEDSPGGPG TSQGRKRRQT SLTDFYHSKR RLVFCKRKP 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning, sequencing, chromosomal localization and expression of mouse p21 (Waf1)."
Huppi K., Siwarski D., Dosik J., Michieli P., Chedid M., Reed S., Mock B., Givol D., Mushinski J.F.
Oncogene 9:3017-3020(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: BXSB.
Tissue: Spleen.
[2]"Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues."
El-Deiry W.S., Tokino T., Waldman T., Velculescu V.E., Oliner J.D., Burell M., Hill D.E., Rees J.L., Hamilton S.R., Kinzler K.W., Vogelstein B.
Cancer Res. 55:2910-2919(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6J.
Tissue: Mammary gland.
[4]"WAF1, a potential mediator of p53 tumor suppression."
El-Deiry W.S., Tokino T., Velculescu V.E., Levy D.B., Parsons R., Trent J.M., Lin D., Mercer W.E., Kinzler K.W., Vogelstein B.
Cell 75:817-825(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-143.
[5]"An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis."
Li Z., Zhang Q., Mao J.H., Weise A., Mrasek K., Fan X., Zhang X., Liehr T., Lu K.H., Balmain A., Cai W.W.
Oncogene 29:2659-2671(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HDAC1, SUBCELLULAR LOCATION, ACETYLATION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U09507 mRNA. Translation: AAB60456.1.
U24173 mRNA. Translation: AAC52220.1.
BC002043 mRNA. Translation: AAH02043.1.
CCDSCCDS28591.1.
PIRA49438.
I49023.
RefSeqNP_001104569.1. NM_001111099.1.
NP_031695.1. NM_007669.4.
UniGeneMm.195663.

3D structure databases

ProteinModelPortalP39689.
SMRP39689. Positions 13-79.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198651. 12 interactions.
DIPDIP-24178N.
IntActP39689. 3 interactions.
MINTMINT-1529153.

PTM databases

PhosphoSiteP39689.

Proteomic databases

PRIDEP39689.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000023829; ENSMUSP00000023829; ENSMUSG00000023067.
ENSMUST00000119901; ENSMUSP00000113150; ENSMUSG00000023067.
ENSMUST00000122348; ENSMUSP00000112411; ENSMUSG00000023067.
GeneID12575.
KEGGmmu:12575.
UCSCuc008bsg.2. mouse.

Organism-specific databases

CTD1026.
MGIMGI:104556. Cdkn1a.

Phylogenomic databases

eggNOGNOG290902.
HOGENOMHOG000285999.
HOVERGENHBG050868.
InParanoidP39689.
KOK06625.
OMAFAWERVW.
OrthoDBEOG7GJ6HD.
PhylomeDBP39689.
TreeFamTF101038.

Gene expression databases

ArrayExpressP39689.
BgeeP39689.
CleanExMM_CDKN1A.
GenevestigatorP39689.

Family and domain databases

InterProIPR003175. CDI.
[Graphical view]
PANTHERPTHR10265. PTHR10265. 1 hit.
PfamPF02234. CDI. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSCDKN1A. mouse.
NextBio281686.
PROP39689.
SOURCESearch...

Entry information

Entry nameCDN1A_MOUSE
AccessionPrimary (citable) accession number: P39689
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: January 23, 2007
Last modified: July 9, 2014
This is version 123 of the entry and version 4 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot