P53_OTOBE
ID P53_OTOBE Reviewed; 314 AA.
AC Q64662;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Cellular tumor antigen p53;
DE AltName: Full=Tumor suppressor p53;
DE Flags: Fragment;
GN Name=TP53;
OS Otospermophilus beecheyi (California ground squirrel) (Spermophilus
OS beecheyi).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Sciuromorpha; Sciuridae;
OC Xerinae; Marmotini; Otospermophilus.
OX NCBI_TaxID=34862;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Thymus;
RX PubMed=7923176;
RA Rivkina M.B., Cullen J.M., Robinson W.S., Marion P.L.;
RT "State of the p53 gene in hepatocellular carcinomas of ground squirrels and
RT woodchucks with past and ongoing infection with hepadnaviruses.";
RL Cancer Res. 54:5430-5437(1994).
CC -!- FUNCTION: Acts as a tumor suppressor in many tumor types; induces
CC growth arrest or apoptosis depending on the physiological circumstances
CC and cell type. Involved in cell cycle regulation as a trans-activator
CC that acts to negatively regulate cell division by controlling a set of
CC genes required for this process. One of the activated genes is an
CC inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be
CC mediated either by stimulation of BAX and FAS antigen expression, or by
CC repression of Bcl-2 expression. Its pro-apoptotic activity is activated
CC via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (By
CC similarity). However, this activity is inhibited when the interaction
CC with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (By
CC similarity). In cooperation with mitochondrial PPIF is involved in
CC activating oxidative stress-induced necrosis; the function is largely
CC independent of transcription. Prevents CDK7 kinase activity when
CC associated to CAK complex in response to DNA damage, thus stopping cell
CC cycle progression. Induces the transcription of long intergenic non-
CC coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21
CC participates in TP53-dependent transcriptional repression leading to
CC apoptosis and seems to have an effect on cell-cycle regulation.
CC Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated
CC transcriptional activation of PER2. {ECO:0000250|UniProtKB:P02340,
CC ECO:0000250|UniProtKB:P04637}.
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250};
CC -!- SUBUNIT: Forms homodimers and homotetramers (By similarity). Binds DNA
CC as a homotetramer. Interacts with AXIN1. Probably part of a complex
CC consisting of TP53, HIPK2 and AXIN1. Interacts with histone
CC acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and
CC recruits them to promoters. Interacts (via C-terminus) with TAF1; when
CC TAF1 is part of the TFIID complex. Interacts with ING4; this
CC interaction may be indirect. Found in a complex with CABLES1 and TP73.
CC Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX.
CC Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with
CC CHD8; leading to recruit histone H1 and prevent transactivation
CC activity. Interacts with ARMC10, BANP, CDKN2AIP, NUAK1, STK11/LKB1,
CC UHRF2 and E4F. Interacts with YWHAZ; the interaction enhances TP53
CC transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits
CC this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-
CC terminus). Interacts with MKRN1. Interacts with PML (via C-terminus).
CC Interacts with MDM2; leading to ubiquitination and proteasomal
CC degradation of TP53. Directly interacts with FBXO42; leading to
CC ubiquitination and degradation of TP53. Interacts with the phosphatase
CC PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent
CC inhibition of cell proliferation. Interacts with PPP2R2A. Interacts
CC with AURKA, DAXX, BRD7 and TRIM24. Interacts with L3MBTL1. Interacts
CC with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in
CC response to DNA damage. Interacts with CDK5 in neurons. Interacts with
CC AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with
CC PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with
CC PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG.
CC Interacts with PPIF; the association implicates preferentially
CC tetrameric TP53, is induced by oxidative stress and is impaired by
CC cyclosporin A (CsA). Interacts with SNAI1; the interaction induces
CC SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-
CC induced cell invasion. Interacts with KAT6A. Interacts with UBC9.
CC Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-
CC binding domain) with ZNF385A; the interaction is direct and enhances
CC p53/TP53 transactivation functions on cell-cycle arrest target genes,
CC resulting in growth arrest (By similarity). Interacts with ANKRD2.
CC Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination.
CC Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus).
CC Interacts with MORC3. Interacts (via C-terminus) with POU4F2 (via C-
CC terminus). Interacts (via oligomerization region) with NOP53; the
CC interaction is direct and may prevent the MDM2-mediated proteasomal
CC degradation of TP53. Interacts with AFG1L; mediates mitochondrial
CC translocation of TP53. Interacts with UBD (By similarity). Interacts
CC with TAF6 (By similarity). Interacts with C10orf90/FATS; the
CC interaction inhibits binding of TP53 and MDM2 (By similarity).
CC Interacts with NUPR1; interaction is stress-dependent. Forms a complex
CC with EP300 and NUPR1; this complex binds CDKN1A promoter leading to
CC transcriptional induction of CDKN1A (By similarity). Interacts with
CC PRMT5 in response to DNA damage; the interaction is TTC5/STRAP
CC dependent (By similarity). Interacts with PPP1R13L (via SH3 domain and
CC ANK repeats); the interaction inhibits pro-apoptotic activity of
CC p53/TP53 (By similarity). Interacts with PPP1R13B/ASPP1 and
CC TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (By
CC similarity). When phosphorylated, interacts with DDX3X and gamma-
CC tubulin (By similarity). Interacts with KAT7/HBO1; leading to inhibit
CC histone acetyltransferase activity of KAT7/HBO1 (By similarity).
CC Interacts with S100A4; this interaction promotes TP53 degradation (By
CC similarity). Interacts with TTC5/STRAP; the interaction may result in
CC increased mitochondrial-dependent apoptosis (By similarity). Interacts
CC with NQO1; this interaction is NADH-dependent, stabilizes TP53 in
CC response to oxidative stress and protects it from ubiquitin-independent
CC degradation by the 20S proteasome. {ECO:0000250|UniProtKB:P02340,
CC ECO:0000250|UniProtKB:P04637, ECO:0000250|UniProtKB:P10361}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P04637}. Nucleus
CC {ECO:0000250|UniProtKB:P04637}. Nucleus, PML body
CC {ECO:0000250|UniProtKB:P04637}. Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:P04637}. Mitochondrion matrix
CC {ECO:0000250|UniProtKB:P04637}. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome {ECO:0000250|UniProtKB:P04637}.
CC Note=Interaction with BANP promotes nuclear localization. Recruited
CC into PML bodies together with CHEK2. Translocates to mitochondria upon
CC oxidative stress. Translocates to mitochondria in response to mitomycin
CC C treatment (By similarity). {ECO:0000250|UniProtKB:P04637}.
CC -!- PTM: Phosphorylated by VRK1, which may prevent the interaction with
CC MDM2. Phosphorylated by CHEK2 in response to DNA damage, which prevents
CC ubiquitination by MDM2. Phosphorylated by PLK3 in response to reactive
CC oxygen species (ROS), promoting p53/TP53-mediated apoptosis.
CC Phosphorylated on Ser-13 by CDK7 in a CAK complex in response to DNA
CC damage. Phosphorylated by CK2 following UV but not gamma irradiation.
CC Stabilized by CDK5-mediated phosphorylation in response to genotoxic
CC and oxidative stresses at Ser-13 and Ser-26, leading to accumulation of
CC p53/TP53, particularly in the nucleus, thus inducing the
CC transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at
CC Ser-26 in response to genotoxic stress. Phosphorylated at Ser-293 by
CC CDK2 in response to DNA-damage (By similarity). {ECO:0000250}.
CC -!- PTM: Monomethylated by SETD7, leading to stabilization and increased
CC transcriptional activation. Monomethylated by SMYD2, leading to
CC decreased DNA-binding activity and subsequent transcriptional
CC regulation activity. Monomethylation by SETD7 prevents interaction with
CC SMYD2 and subsequent monomethylation by SMYD2 (By similarity).
CC Dimethylated by EHMT1 and EHMT2. Monomethylated by KMT5A, promoting
CC interaction with L3MBTL1 and leading to repress transcriptional
CC activity. Demethylation by KDM1A prevents interaction with TP53BP1 and
CC represses TP53-mediated transcriptional activation (By similarity).
CC Monomethylated at Arg-311 and dimethylated at Arg-313 by PRMT5;
CC methylation is increased after DNA damage and might possibly affect
CC TP53 target gene specificity (By similarity).
CC {ECO:0000250|UniProtKB:P04637}.
CC -!- PTM: Sumoylated with SUMO1. {ECO:0000250}.
CC -!- PTM: Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal
CC degradation. Ubiquitinated by RFWD3, which works in cooperation with
CC MDM2 and may catalyze the formation of short polyubiquitin chains on
CC p53/TP53 that are not targeted to the proteasome. Ubiquitinated by
CC MKRN1, which leads to proteasomal degradation. Deubiquitinated by
CC USP10, leading to stabilize it. Ubiquitinated by TRIM24, RFFL, RNF34
CC and RNF125, which leads to proteasomal degradation. Ubiquitination by
CC TOPORS induces degradation. Deubiquitination by USP7, leading to
CC stabilize it. Ubiquitinated by COP1, which leads to proteasomal
CC degradation (By similarity). Ubiquitination and subsequent proteasomal
CC degradation is negatively regulated by CCAR2 (By similarity).
CC Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-
CC linkage independent and non-proteolytic, leading to TP53 stabilization
CC (By similarity). {ECO:0000250|UniProtKB:P02340,
CC ECO:0000250|UniProtKB:P04637}.
CC -!- DISEASE: Note=p53 is found in increased amounts in a wide variety of
CC transformed cells. p53 is frequently mutated or inactivated in many
CC types of cancer.
CC -!- SIMILARITY: Belongs to the p53 family. {ECO:0000305}.
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DR EMBL; U43902; AAA85628.1; -; mRNA.
DR AlphaFoldDB; Q64662; -.
DR SMR; Q64662; -.
DR GO; GO:0005813; C:centrosome; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:1990841; F:promoter-specific chromatin binding; ISS:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0048512; P:circadian behavior; ISS:UniProtKB.
DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0051262; P:protein tetramerization; IEA:InterPro.
DR CDD; cd08367; P53; 1.
DR Gene3D; 2.60.40.720; -; 1.
DR Gene3D; 4.10.170.10; -; 1.
DR InterPro; IPR008967; p53-like_TF_DNA-bd.
DR InterPro; IPR012346; p53/RUNT-type_TF_DNA-bd_sf.
DR InterPro; IPR011615; p53_DNA-bd.
DR InterPro; IPR036674; p53_tetramer_sf.
DR InterPro; IPR002117; p53_tumour_suppressor.
DR PANTHER; PTHR11447; PTHR11447; 1.
DR Pfam; PF00870; P53; 1.
DR PRINTS; PR00386; P53SUPPRESSR.
DR SUPFAM; SSF49417; SSF49417; 1.
DR PROSITE; PS00348; P53; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Activator; Apoptosis; Biological rhythms; Cell cycle;
KW Cytoplasm; Cytoskeleton; DNA-binding; Endoplasmic reticulum;
KW Isopeptide bond; Metal-binding; Methylation; Mitochondrion; Necrosis;
KW Nucleus; Phosphoprotein; Repressor; Transcription;
KW Transcription regulation; Tumor suppressor; Ubl conjugation; Zinc.
FT CHAIN <1..>314
FT /note="Cellular tumor antigen p53"
FT /id="PRO_0000185714"
FT DNA_BIND 80..270
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT REGION <1..24
FT /note="Transcription activation (acidic)"
FT REGION 44..88
FT /note="Interaction with WWOX"
FT /evidence="ECO:0000250"
FT REGION 78..278
FT /note="Required for interaction with ZNF385A"
FT /evidence="ECO:0000250"
FT REGION 91..214
FT /note="Required for interaction with FBXO42"
FT /evidence="ECO:0000250"
FT REGION 234..272
FT /note="Interaction with E4F1"
FT /evidence="ECO:0000250"
FT REGION 251..258
FT /note="Interaction with DNA"
FT /evidence="ECO:0000250"
FT REGION 261..306
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 303..>314
FT /note="Oligomerization"
FT MOTIF 283..299
FT /note="Bipartite nuclear localization signal"
FT /evidence="ECO:0000250"
FT BINDING 154
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT BINDING 157
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT BINDING 216
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT BINDING 220
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT SITE 98
FT /note="Interaction with DNA"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 13
FT /note="Phosphoserine; by CDK5 and CDK7"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 17
FT /note="Phosphoserine; by MAPKAPK5"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 26
FT /note="Phosphoserine; by CDK5, DYRK2, HIPK2 and PKC/PRKCG"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 98
FT /note="N6-acetyllysine; by KAT6A"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 161
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 247
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 262
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 283
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 293
FT /note="Phosphoserine; by AURKA, CDK1 and CDK2"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 299
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P02340"
FT MOD_RES 311
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT MOD_RES 313
FT /note="Symmetric dimethylarginine"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT CROSSLNK 269
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P04637"
FT NON_TER 1
FT NON_TER 314
SQ SEQUENCE 314 AA; 34618 MW; 4F949656A8BED1F6 CRC64;
DLWNLLPENN VLSPVLSPPM DDLLLSSEDV ENWFDKGPDE ALQMSAAPAP KAPTPAASTL
AAPTPAISWP LSSSVPSQNT YPGVYGFRLG FIHSGTAKSV TCTYSPSLNK LFCQLAKTCP
VQLWVDSTPP PGTRVRAMAI YKKSQHMTEV VRRCPHHERC SDSDGLAPPQ HLIRVEGNLR
AEYLDDRNTF RHSVVVPYEP PEVGSESTTI HYNYMCNSSC MGGMNRRPIL TIITLEDSSG
NLLGRNSFEV RVCACPGRDR RTEEENFRKR GEPCPEPPPG STKRALPTGT NSSPQPKKKP
LDGEYFTLKI RGRA
