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cellular tumor antigen p53; tumor suppressor p53, phosphoprotein p53; antigen NY-CO-13 (TP53, p53)

Function: - acts as a tumor suppressor in many tumor types - induces growth arrest or apoptosis depending on physiological circumstances & cell type - involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process - one of the activated genes is an inhibitor of cyclin-dependent kinases - apoptosis induction seems to be mediated either by stimulation of BAX & FAS antigen expression, or by repression of Bcl-2 expression - p53 inhibits transcription from TATA box-containing genes - roles in arresting cells in G1 & mediating apoptosis as cells lacking p53 do not arrest in G1 & do not undergo apoptosis in response to DNA damage - p53 can be activated by DNA damage (double strand breaks, DNA repair intermediates), hypoxia, ribonucleoside triphosphate levels below a critical threshold - p53 activates transcription of several genes including p21Waf1/Cip1 which inhibits cyclin-dependent kinase (CDK) mediated phosphorylation of Rb & dissociation of the Rb/E2F complex; the E2F freed from Rb then activates transcription of S-phase specific genes [8] - other genes activated by p53 include: bax, creatine kinase M subunit, cyclin G, gadd 45, mdm2, 14-3-3 sigma, p53-AIP1, p53-R2 & reprimo - p53 is also a component of the spindle checkpoint that ensures maintenance of diploidy - p53 may associate with the DNA replication complex. - p53 represses transcription of some genes including those for map4, DNA topoisomerase 2 alpha, DP-1, wee1, stathmin & presenilin 1 [13] - p53 associates with mSin3a & histone deacetylase in a transcriptional repression complex [13]. - when p53 is induced by hypoxia, it functions as a repressor for map4 & stathmin genes but does not activate bax & p21Waf1/Cip1 [13] - interacts with AXIN1 - probably part of a complex consisting of TP53, HIPK2 & AXIN1 (putative) - binds DNA as a homotetramer - interacts with histone acetyltransferases EP300 & methyltransferases HRMT1L2 & CARM1, & recruits them to promoters - C-terminus interacts with TAF1, when TAF1 is part of the TFIID complex - interacts with ING4 & this interaction may be indirect found in a complex with CABLES1 & TP73 - interacts with HIPK1, HIPK2, & P53DINP1 - interacts with WWOX - may interacts with HCV core protein - interacts with USP7 & SYVN1 - interacts with HSP90AB1 (putative) - interacts with BANP, CDKN2AIP & E4F1 acetylated - acetylation of Lys-382 by CREBBP enhances transcriptional activity - deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program & modulate cell senescence - phosphorylation on Ser residues mediates transcriptional activation - phosphorylated by HIPK1 (putative) - phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter - phosphorylated on Thr-18 by VRK1, which may prevent the interaction with MDM2 - phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation - phosphorylated on Ser-46 by HIPK2 upon UV irradiation - phosphorylation on Ser-46 is required for acetylation by CREBBP - phosphorylated on Ser-392 following UV but not gamma irradiation - phosphorylated upon DNA damage, probably by ATM or ATR - phosphorylated on Ser-15 upon ultraviolet irradiation; which is enhanced by interaction with BANP - dephosphorylated by PP2A - ubiquitinated by SYVN1, which leads to proteasomal degradation - monomethylated at Lys-372 by SETD7, leading to stabilize it & increase transcriptional activation - monomethylated at Lys-370 by SMYD2, leading to decrease DNA-binding activity & subsequent transcriptional regulation activity - Lys-372 monomethylation prevents interaction with SMYD2 & subsequenct monomethylation at Lys-370 Cofactor: binds 1 Zn+2 per subunit Structure: - nuclear export signal acts as a transcriptional repression domain - belongs to the p53 family Compartment: - cytoplasm, nucleus, endoplasmic reticulum - interaction with BANP promotes nuclear localization Alternative splicing: - named isoforms=2; - one isoform seems to be non-functional Expression: - expressed in quiescent lymphocytes Pathology: - p53 binds to SV40 large T antigen, adenovirus E1b & papilloma virus E6 proteins - deficiency of p53 is associated with tetraploidy in vivo [7] - in vitro, interaction of TP53 with cancer-associated/HPV (E6) viral proteins leads to ubiquitination & degradation of TP53 giving a possible model for cell growth regulation; this complex formation requires an additional factor, E6-AP, which stably associates with TP53 in presence of E6 - SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A may be O-glycosylated in the C-terminal basic region - defects in TP53 are a cause of Li-Fraumeni syndrome - TP53 is found in increased amounts in a wide variety of transformed cells - TP53 is frequently mutated or inactivated in about 60% of cancers - defects in TP53 are involved in a) esophageal squamous cell carcinoma b) nasopharyngeal carcinoma c) head & neck squamous cell carcinoma d) oral squamous cell carcinoma e) lung cancer f) choroid plexus papilloma g) one form of hereditary adrenocortical carcinoma h) Barrett metaplasia Genetics: - mice heterozygous or homozygous for a p53 mutation are viable, but develop a variety of tumors [9] - the most common neoplasms in p53-deficient mice are sarcomas & lymphomas - germline homozygosity for p53 mutation causes neoplasms in 90% of mice by 6 months of age - mutant mice heterozygous for both p53 & Rb mutation have reduced viablility & exhibit novel pathology including retinal dysplasia & increased tumor load & metastatic spread Laboratory: - protein p53 Ab in serum/plasma Note: - see motifs in linr drawing for further description of functional domains

Interactions

molecular events

Related

apoptosis stimulating protein of p53; p53-binding protein (ASPP) E3 ubiquitin-protein ligase Mdm2; p53-binding protein Mdm2; oncoprotein Mdm2; double minute 2 protein; Hdm2 (MDM2) Li-Fraumeni syndrome neoplasms in which p53 mutations have been found p53 gene TP53 gene mutation

Specific

p53 induced genes

General

anti-oncoprotein (tumor suppressor protein) p53 family protein phosphoprotein pro apoptotic protein

Properties

CONFIGURATION: tetramer SIZE: MW = 44 kD entity length = 393 aa COMPARTMENT: cytoplasm cell nucleus endoplasmic reticulum MOTIF: transcriptional activation domain SITE: 1-42 MOTIF: Ser phosphorylation site {S9} Ser phosphorylation site {S15} FOR-PHOSPHORYLATION-BY: double-stranded DNA-dependent protein kinase casein kinase 1 binding site SITE: 13-29 FOR-BINDING-OF: E3 ubiquitin-protein ligase Mdm2 Thr phosphorylation site {T18} Ser phosphorylation site {S20} FOR-PHOSPHORYLATION-BY: checkpoint kinase 2 (CHK2) Ser phosphorylation site {S33} Ser phosphorylation site {S37} FOR-PHOSPHORYLATION-BY: double-stranded DNA-dependent protein kinase binding site SITE: 40-160 FOR-BINDING-OF: paired amphipathic helix protein sin3a MOTIF: Ser phosphorylation site {S46} Thr phosphorylation site {T55} proline-rich transcriptional activation domain (TAD) SITE: 61-94 MOTIF: proline residue (SEVERAL) Ser phosphorylation site {S99} DNA-binding motif SITE: 102-292 MOTIF: Zn+2-binding site SITE: 176-176 Zn+2-binding site SITE: 179-179 Zn+2-binding site SITE: 238-238 53BP2 SH3 interaction {241-248} Zn+2-binding site SITE: 242-242 nuclear translocation signal {305-321} MOTIF: Ser phosphorylation site {S315} FOR-PHOSPHORYLATION-BY: cyclin-dependent kinase-1 HIPK2 interaction {319-360} basic region {319-392} MOTIF: binding site SITE: 324-355 EFFECTOR-BOUND: cellular tumor antigen p53 BOUND-VIA: binding site nuclear export signal {339-350} USP7 interaction {359-363} [KR]-[STA]-K {370-372} Ser phosphorylation site {S376} FOR-PHOSPHORYLATION-BY: protein kinase C Ser phosphorylation site {S378} FOR-PHOSPHORYLATION-BY: protein kinase C Ser phosphorylation site {S392} FOR-PHOSPHORYLATION-BY: casein kinase 2 MISC-INFO: 1/2life 20 MIN

References

  1. Wilcock D, Lane DP. Localization of p53, retinoblastoma and host replication proteins at sites of viral replication in herpes-infected cells. Nature. 1991 Jan 31;349(6308):429-31. PMID: 1671528
  2. Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249-70. Review. PMID: 1988147
  3. Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215-21. PMID: 1552940
  4. Lane DP. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15-6. PMID: 1614522
  5. Mack DH, Vartikar J, Pipas JM, Laimins LA. Specific repression of TATA-mediated but not initiator- mediated transcription by wild-type p53. Nature. 1993 May 20;363(6426):281-3. PMID: 8387645
  6. Gottlieb TM, Jackson SP. Protein kinases and DNA damage. Trends Biochem Sci. 1994 Nov;19(11):500-3. Review. PMID: 7855895
  7. Cross SM, Sanchez CA, Morgan CA, Schimke MK, Ramel S, Idzerda RL, Raskind WH, Reid BJ. A p53-dependent mouse spindle checkpoint. Science. 1995 Mar 3;267(5202):1353-6. PMID: 7871434
  8. Enoch T, Norbury C. Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. Trends Biochem Sci. 1995 Oct;20(10):426-30. Review. PMID: 8533157
  9. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545-60. Review. PMID: 7677168
  10. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997 Feb 7;88(3):323-31. Review. PMID: 9039259
  11. Lee S, Elenbaas B, Levine A, Griffith J. p53 and its 14 kDa C-terminal domain recognize primary DNA damage in the form of insertion/deletion mismatches. Cell. 1995 Jun 30;81(7):1013-20. PMID: 7600570
  12. Shieh SY, Ikeda M, Taya Y, Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell. 1997 Oct 31;91(3):325-34. PMID: 9363941
  13. Murphy M, Ahn J, Walker KK, Hoffman WH, Evans RM, Levine AJ, George DL. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 1999 Oct 1;13(19):2490-501. PMID: 10521394
  14. IARC TP53 mutation database; Note: Somatic and germline TP53 mutations in human cancers http://www-p53.iarc.fr/
  15. 53 web site at the institut Curie http://p53.free.fr/
  16. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/P53ID88.html
  17. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=TP53
  18. SHMPD: The Singapore human mutation and polymorphism database http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=TP53
  19. Wikipedia; Note: P53 entry http://en.wikipedia.org/wiki/P53
  20. UniProt :accession P04637
  21. Entrez Gene :accession 7157

Component-of

molecular complex

Databases & Figures

OMIM correlations MORBIDMAP 191170 UniProt P04637 PFAM correlations Entrez Gene 7157 KEGG correlations Figures/diagrams/slides/tables related to cellular tumor antigen p53