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P39689

- CDN1A_MOUSE

UniProt

P39689 - CDN1A_MOUSE

Protein

Cyclin-dependent kinase inhibitor 1

Gene

Cdkn1a

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
  1. 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: Ensembl
    3. cyclin-dependent protein serine/threonine kinase inhibitor activity Source: MGI
    4. metal ion binding Source: UniProtKB-KW
    5. protein binding Source: IntAct

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

    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.

    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. nucleus Source: MGI
    5. PCNA-p21 complex Source: UniProtKB

    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 residuei112 – 1121Phosphoserine; by GSK3-betaBy similarity
    Modified residuei125 – 1251PhosphoserineBy similarity
    Modified residuei140 – 1401Phosphothreonine; by PKA; PKB/AKT1; PIM1 and PIM2By similarity
    Modified residuei141 – 1411PhosphoserineBy similarity

    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.By similarity
    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

    ArrayExpressiP39689.
    BgeeiP39689.
    CleanExiMM_CDKN1A.
    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.By similarity

    Binary interactionsi

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

    Protein-protein interaction databases

    BioGridi198651. 14 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.
    [Graphical view]
    PANTHERiPTHR10265. PTHR10265. 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

    MSNPGDVRPV PHRSKVCRCL FGPVDSEQLR RDCDALMAGC LQEARERWNF    50
    DFVTETPLEG NFVWERVRSL GLPKVYLSPG SRSRDDLGGD KRPSTSSALL 100
    QGPAPEDHVA LSLSCTLVSE RPEDSPGGPG TSQGRKRRQT SLTDFYHSKR 150
    RLVFCKRKP 159
    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:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U09507 mRNA. Translation: AAB60456.1 .
    U24173 mRNA. Translation: AAC52220.1 .
    BC002043 mRNA. Translation: AAH02043.1 .
    CCDSi CCDS28591.1.
    PIRi A49438.
    I49023.
    RefSeqi NP_001104569.1. NM_001111099.1.
    NP_031695.1. NM_007669.4.
    UniGenei Mm.195663.

    3D structure databases

    ProteinModelPortali P39689.
    SMRi P39689. Positions 13-79.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 198651. 14 interactions.
    DIPi DIP-24178N.
    IntActi P39689. 3 interactions.
    MINTi MINT-1529153.

    PTM databases

    PhosphoSitei P39689.

    Proteomic databases

    PRIDEi P39689.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000023829 ; ENSMUSP00000023829 ; ENSMUSG00000023067 .
    ENSMUST00000119901 ; ENSMUSP00000113150 ; ENSMUSG00000023067 .
    ENSMUST00000122348 ; ENSMUSP00000112411 ; ENSMUSG00000023067 .
    GeneIDi 12575.
    KEGGi mmu:12575.
    UCSCi uc008bsg.2. mouse.

    Organism-specific databases

    CTDi 1026.
    MGIi MGI:104556. Cdkn1a.

    Phylogenomic databases

    eggNOGi NOG290902.
    HOGENOMi HOG000285999.
    HOVERGENi HBG050868.
    InParanoidi P39689.
    KOi K06625.
    OMAi FAWERVW.
    OrthoDBi EOG7GJ6HD.
    PhylomeDBi P39689.
    TreeFami TF101038.

    Enzyme and pathway databases

    Reactomei REACT_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.

    Miscellaneous databases

    ChiTaRSi CDKN1A. mouse.
    NextBioi 281686.
    PROi P39689.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P39689.
    Bgeei P39689.
    CleanExi MM_CDKN1A.
    Genevestigatori P39689.

    Family and domain databases

    InterProi IPR003175. CDI.
    [Graphical view ]
    PANTHERi PTHR10265. PTHR10265. 1 hit.
    Pfami PF02234. CDI. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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.

    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: October 1, 2014
    This is version 125 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