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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 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).By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri12 – 4029C4-typeSequence AnalysisAdd
BLAST

GO - Molecular functioni

  1. cyclin binding Source: MGI
  2. cyclin-dependent protein kinase activating kinase activity Source: MGI
  3. cyclin-dependent protein serine/threonine kinase inhibitor activity Source: MGI
  4. metal ion binding Source: UniProtKB-KW
  5. ubiquitin protein ligase binding Source: MGI

GO - Biological processi

  1. cell cycle arrest Source: MGI
  2. cellular response to DNA damage stimulus Source: MGI
  3. cellular response to extracellular stimulus Source: MGI
  4. cellular response to heat Source: Ensembl
  5. cellular response to ionizing radiation Source: MGI
  6. cellular response to UV-B Source: UniProtKB
  7. cellular senescence Source: MGI
  8. DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest Source: MGI
  9. G1/S transition of mitotic cell cycle Source: MGI
  10. G2/M transition of mitotic cell cycle Source: MGI
  11. intestinal epithelial cell maturation Source: Ensembl
  12. intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Source: MGI
  13. mitotic cell cycle arrest Source: MGI
  14. negative regulation of apoptotic process Source: Ensembl
  15. negative regulation of cell growth Source: MGI
  16. negative regulation of cell proliferation Source: MGI
  17. negative regulation of cyclin-dependent protein serine/threonine kinase activity Source: MGI
  18. negative regulation of G1/S transition of mitotic cell cycle Source: MGI
  19. negative regulation of gene expression Source: MGI
  20. negative regulation of phosphorylation Source: MGI
  21. organ regeneration Source: Ensembl
  22. positive regulation of B cell proliferation Source: MGI
  23. positive regulation of fibroblast proliferation Source: MGI
  24. positive regulation of programmed cell death Source: MGI
  25. positive regulation of protein kinase activity Source: MGI
  26. positive regulation of reactive oxygen species metabolic process Source: MGI
  27. protein phosphorylation Source: MGI
  28. Ras protein signal transduction Source: Ensembl
  29. regulation of cell cycle Source: MGI
  30. regulation of cyclin-dependent protein serine/threonine kinase activity Source: MGI
  31. regulation of DNA biosynthetic process Source: MGI
  32. regulation of mitotic cell cycle Source: MGI
  33. regulation of protein import into nucleus, translocation Source: MGI
  34. response to arsenic-containing substance Source: Ensembl
  35. response to corticosterone Source: Ensembl
  36. response to drug Source: Ensembl
  37. response to hyperoxia Source: Ensembl
  38. response to organonitrogen compound Source: Ensembl
  39. response to toxic substance Source: Ensembl
  40. response to UV Source: MGI
  41. 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

ReactomeiREACT_188819. DNA Damage/Telomere Stress Induced Senescence.
REACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
REACT_206033. Senescence-Associated Secretory Phenotype (SASP).
REACT_220647. SCF(Skp2)-mediated degradation of p27/p21.
REACT_220918. AKT phosphorylates targets in the cytosol.
REACT_223647. Cyclin A:Cdk2-associated events at S phase entry.
REACT_245230. Orc1 removal from chromatin.
REACT_246476. Regulation of APC/C activators between G1/S and early anaphase.
REACT_257943. p53-Dependent G1 DNA Damage Response.
REACT_258573. Cyclin D associated events in G1.

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
ProteomesiUP000000589: Chromosome 17

Organism-specific databases

MGIiMGI:104556. Cdkn1a.

Subcellular locationi

Cytoplasm By similarity. Nucleus 1 Publication

GO - Cellular componenti

  1. cyclin-dependent protein kinase holoenzyme complex Source: MGI
  2. cytoplasm Source: MGI
  3. cytosol Source: MGI
  4. intracellular membrane-bounded organelle Source: MGI
  5. nucleoplasm Source: MGI
  6. nucleus Source: MGI
  7. PCNA-p21 complex Source: UniProtKB
  8. perinuclear region of cytoplasm Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 159158Cyclin-dependent kinase inhibitor 1PRO_0000190080Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserineBy similarity
Cross-linki2 – 2Glycyl serine ester (Ser-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei78 – 781Phosphoserine; by NUAK11 Publication
Modified residuei112 – 1121Phosphoserine; by GSK3-betaBy similarity
Modified residuei125 – 1251PhosphoserineBy similarity
Modified residuei140 – 1401Phosphothreonine; by PKA; PKB/AKT1; PIM1 and PIM2By similarity
Modified residuei141 – 1411Phosphoserine; by NUAK11 Publication

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

PRIDEiP39689.

PTM databases

PhosphoSiteiP39689.

Expressioni

Inductioni

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

Gene expression databases

BgeeiP39689.
CleanExiMM_CDKN1A.
ExpressionAtlasiP39689. baseline and differential.
GenevestigatoriP39689.

Interactioni

Subunit structurei

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). Interacts with STK11. Interacts with NUAK1 (By similarity).By similarity2 Publications

Binary interactionsi

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

Protein-protein interaction databases

BioGridi198651. 15 interactions.
DIPiDIP-24178N.
IntActiP39689. 3 interactions.
MINTiMINT-1529153.

Structurei

3D structure databases

ProteinModelPortaliP39689.
SMRiP39689. Positions 13-79.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni17 – 248Required for binding cyclinsBy similarity
Regioni53 – 586Required for binding CDKsBy similarity

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi135 – 15925PIP-box K+4 motifAdd
BLAST

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 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

Sequence similaritiesi

Belongs to the CDI family.Curated

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri12 – 4029C4-typeSequence AnalysisAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiNOG290902.
HOGENOMiHOG000285999.
HOVERGENiHBG050868.
InParanoidiP39689.
KOiK06625.
OMAiFAWERVW.
OrthoDBiEOG7GJ6HD.
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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti30 – 301R → S no nucleotide entry (PubMed:8242752).Curated
Sequence conflicti56 – 572TP → RQ no nucleotide entry (PubMed:8242752).Curated

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_001111099.1.
NP_031695.1. NM_007669.4.
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_001111099.1.
NP_031695.1. NM_007669.4.
UniGeneiMm.195663.

3D structure databases

ProteinModelPortaliP39689.
SMRiP39689. Positions 13-79.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198651. 15 interactions.
DIPiDIP-24178N.
IntActiP39689. 3 interactions.
MINTiMINT-1529153.

PTM databases

PhosphoSiteiP39689.

Proteomic databases

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

eggNOGiNOG290902.
HOGENOMiHOG000285999.
HOVERGENiHBG050868.
InParanoidiP39689.
KOiK06625.
OMAiFAWERVW.
OrthoDBiEOG7GJ6HD.
PhylomeDBiP39689.
TreeFamiTF101038.

Enzyme and pathway databases

ReactomeiREACT_188819. DNA Damage/Telomere Stress Induced Senescence.
REACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
REACT_206033. Senescence-Associated Secretory Phenotype (SASP).
REACT_220647. SCF(Skp2)-mediated degradation of p27/p21.
REACT_220918. AKT phosphorylates targets in the cytosol.
REACT_223647. Cyclin A:Cdk2-associated events at S phase entry.
REACT_245230. Orc1 removal from chromatin.
REACT_246476. Regulation of APC/C activators between G1/S and early anaphase.
REACT_257943. p53-Dependent G1 DNA Damage Response.
REACT_258573. Cyclin D associated events in G1.

Miscellaneous databases

ChiTaRSiCdkn1a. mouse.
NextBioi281686.
PROiP39689.
SOURCEiSearch...

Gene expression databases

BgeeiP39689.
CleanExiMM_CDKN1A.
ExpressionAtlasiP39689. baseline and differential.
GenevestigatoriP39689.

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...

Publicationsi

« Hide 'large scale' publications
  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. 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.
  6. Cited for: FUNCTION, INTERACTION WITH STK11, PHOSPHORYLATION AT SER-78 AND SER-141.

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: March 4, 2015
This is version 130 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

External Data

Dasty 3

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 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.