Pathway Map Details

Transcription_P53 signaling pathway



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Object list (links open in MetaCore):

p14ARF, p21, MAP4, beta-Catenin, MEK4(MAP2K4), C-FOS, P300, MKP-7, MDM2, APEX, PIAS2, MKP-1, p53, XPA, ATR, FHL2, CDK2, TDG, CBP, Bcl-2, PCAF, MMP-2, PIAS1, Core complex of TFIIH, MTA2, VEGFR-2, XPC, Histone deacetylase class I, E2F1, VEGFR-1, SUMO-1, NF-KB, MEKK1(MAP3K1), JNK(MAPK8-10), ATM, HSP27, RanBP2, VEGF-A, Rb protein

Description:

p 53 signaling pathway

The Tumor protein p53 ( p53 ) plays a critical role in safeguarding the integrity of the genome. Upon activation, p53 binds to the enhancer/promoter elements of downstream target genes and regulates their transcription, through which it initiates cellular programs that account for most of its tumor-suppressor functions [1].

The signal transduction circuit of p53 consists of the upstream mediators, the core regulation components and the downstream effectors.

The core regulatory circuitry consists of Mdm2 p53 binding protein homolog ( MDM2 ), Cyclin-dependent kinase inhibitor 2A ( p14ARF ) and E2F transcription factor 1 ( E2F1 ). p53 activates MDM2 transcription [1]. MDM2 in conjunction with Proteasome 26S subunit non-ATPase 10 (( PSMD10 (Gankyrin) ) mediates p53 ubiquitination and degradation [1], [2]. E2F1 activates transcription of p53 and p14ARF. p14ARF facilitates proteolytic degradation of E2F1 and MDM2 -mediated p53 ubiquitination [3], [1]. Transcription of p53 is also mediated by nuclear factor kappaB ( NF-KB ) in a response to stress [4].

MDM2 is regulated by sumoylation during nuclear translocation by RAN binding protein 2 ( RanBP2 ) and then further sumoylated in the nucleus by protein inhibitor of activated STAT 1 and 2 ( PIAS1 and PIAS2 ) [5]. MDM2 is a subject for self-ubiquitination. Ubiquitination leads to impairment of MDM2 ubiquitin activity for p53. Association of MDM2 with SMT3 suppressor of mif two 3 homolog 1 ( SUMO-1 ) protects MDM2 from ubiquitination. This increase ubiquitination and degradation of p53 [6]. Retinoblastoma 1 ( Rb protein ) binds to MDM2 and inhibits its activity in PSMD10 - dependent manner resulting in stabilization of p53 [2]. P53 in turn is able to transcriptionally activate Rb protein [7]. Also, Rb protein participates in p53 -mediated regulation of G2 checkpoint [8].

E1A binding protein p300 ( p300 ), CREB binding protein ( CBP ) and K(lysine) acetyltransferase 2B ( PCAF ) regulate p53 transcriprional activity via acetylation. p300 and CBP -dependent acethylation and stabilization of p53 is important after DNA damage. Also, p300 indirectly participates in p53 degradation. Possibly it plays a scaffolding role in p53 ubiquitination by bringing together the p53 ubiquitination target and the MDM2 in unstressed, cycling cells [9], [10]. MDM2 in this case also inhibits p300 acethylation of p53 [11]. The deacetylation of p53 is mediated by the Histone deacetylase class I complex, Deacetylation results in the repression p53 -dependent transcriptional activation [12].

P53 is phosphorylated by Ataxia telangiectasia mutated ( ATM ) in response to DNA damage [13]. Also, Mitogen-activated protein ( JNK(MAPK8-10) ) associates with p53 and phosphorylates it [14], [15]. Phosphorylation of p53 activates p53 through three mechanisms: stabilizing it by disrupting p53 - Mdm2 interaction; regulating p53 transactivation activity; promoting p53 nuclear localization [1]. Interaction of p53 with APEX nuclease ( APEX ) leads to the activation of p53 that possibly does not require covalent modification of the p53 protein [16].

P53 regulates expression of numerous genes. P53 activates expression of Matrix metallopeptidase 2 ( MMP-2 ) [17], Heat shock 27kDa protein 2 ( HSP27 ) [18], Four and a half LIM domains 2 ( FHL2 ) [19], a known Coactivator of beta-Catenin [20]. The p53 is an important mediator of the cellular response to ultraviolet-irradiation induced DNA damage and affects the efficiency of the nucleotide excision repair pathway via regulation of Xeroderma pigmentosum, complementation group C ( XPC ) expression, which is involved in DNA damage recognition [21], [22]. P53 regulates expression of V-fos FBJ murine osteosarcoma viral oncogene homolog ( C-FOS ) [23], [24]. Inhibition of Microtubule-associated protein 4 ( MAP4 ) can reduce microtubule polymerization [25].

References:

  1. Jin S, Levine AJ
    The p53 functional circuit. Journal of cell science 2001 Dec;114(Pt 23):4139-40
  2. Qiu W, Wu J, Walsh EM, Zhang Y, Chen CY, Fujita J, Xiao ZX
    Retinoblastoma protein modulates gankyrin-MDM2 in regulation of p53 stability and chemosensitivity in cancer cells. Oncogene 2008 Jul 3;27(29):4034-43
  3. Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z
    Mdm2 association with p53 targets its ubiquitination. Oncogene 1998 Nov 12;17(19):2543-7
  4. Wu H, Lozano G
    NF-kappa B activation of p53. A potential mechanism for suppressing cell growth in response to stress. The Journal of biological chemistry 1994 Aug 5;269(31):20067-74
  5. Miyauchi Y, Yogosawa S, Honda R, Nishida T, Yasuda H
    Sumoylation of Mdm2 by protein inhibitor of activated STAT (PIAS) and RanBP2 enzymes. The Journal of biological chemistry 2002 Dec 20;277(51):50131-6
  6. Buschmann T, Fuchs SY, Lee CG, Pan ZQ, Ronai Z
    SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53. Cell 2000 Jun 23;101(7):753-62
  7. Osifchin NE, Jiang D, Ohtani-Fujita N, Fujita T, Carroza M, Kim SJ, Sakai T, Robbins PD
    Identification of a p53 binding site in the human retinoblastoma susceptibility gene promoter. The Journal of biological chemistry 1994 Mar 4;269(9):6383-9
  8. Flatt PM, Tang LJ, Scatena CD, Szak ST, Pietenpol JA
    p53 regulation of G(2) checkpoint is retinoblastoma protein dependent. Molecular and cellular biology 2000 Jun;20(12):4210-23
  9. Yuan ZM, Huang Y, Ishiko T, Nakada S, Utsugisawa T, Shioya H, Utsugisawa Y, Yokoyama K, Weichselbaum R, Shi Y, Kufe D
    Role for p300 in stabilization of p53 in the response to DNA damage. The Journal of biological chemistry 1999 Jan 22;274(4):1883-6
  10. Grossman SR
    p300/CBP/p53 interaction and regulation of the p53 response. European journal of biochemistry / FEBS 2001 May;268(10):2773-8
  11. Wang Q, Yang Y, Wang L, Zhang PZ, Yu L
    Acidic domain is indispensable for MDM2 to negatively regulate the acetylation of p53. Biochemical and biophysical research communications 2008 Sep 26;374(3):437-41
  12. Luo J, Su F, Chen D, Shiloh A, Gu W
    Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 2000 Nov 16;408(6810):377-81
  13. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y
    Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 1998 Sep 11;281(5383):1674-7
  14. Hu MC, Qiu WR, Wang YP
    JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases. Oncogene 1997 Nov 6;15(19):2277-87
  15. Oleinik NV, Krupenko NI, Krupenko SA
    Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene 2007 Nov 8;26(51):7222-30
  16. Woods DB, Vousden KH
    Regulation of p53 function. Experimental cell research 2001 Mar 10;264(1):56-66
  17. Bian J, Sun Y
    Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter. Molecular and cellular biology 1997 Nov;17(11):6330-8
  18. Gao C, Zou Z, Xu L, Moul J, Seth P, Srivastava S
    p53-dependent induction of heat shock protein 27 (HSP27) expression. International journal of cancer. Journal international du cancer. 2000 Oct 15;88(2):191-4
  19. Scholl FA, McLoughlin P, Ehler E, de Giovanni C, Schafer BW
    DRAL is a p53-responsive gene whose four and a half LIM domain protein product induces apoptosis. The Journal of cell biology 2000 Oct 30;151(3):495-506
  20. Wei Y, Renard CA, Labalette C, Wu Y, Levy L, Neuveut C, Prieur X, Flajolet M, Prigent S, Buendia MA
    Identification of the LIM protein FHL2 as a coactivator of beta-catenin. The Journal of biological chemistry 2003 Feb 14;278(7):5188-94
  21. Fitch ME, Cross IV, Ford JM
    p53 responsive nucleotide excision repair gene products p48 and XPC, but not p53, localize to sites of UV-irradiation-induced DNA damage, in vivo. Carcinogenesis 2003 May;24(5):843-50
  22. Harms K, Nozell S, Chen X
    The common and distinct target genes of the p53 family transcription factors. Cellular and molecular life sciences : CMLS 2004 Apr;61(7-8):822-42
  23. Ginsberg D, Mechta F, Yaniv M, Oren M
    Wild-type p53 can down-modulate the activity of various promoters. Proceedings of the National Academy of Sciences of the United States of America 1991 Nov 15;88(22):9979-83
  24. Elkeles A, Juven-Gershon T, Israeli D, Wilder S, Zalcenstein A, Oren M
    The c-fos proto-oncogene is a target for transactivation by the p53 tumor suppressor. Molecular and cellular biology 1999 Apr;19(4):2594-600
  25. Bash-Babula J, Toppmeyer D, Labassi M, Reidy J, Orlick M, Senzon R, Alli E, Kearney T, August D, Shih W, Yang JM, Hait WN
    A Phase I/pilot study of sequential doxorubicin/vinorelbine: effects on p53 and microtubule-associated protein 4. Clinical cancer research : an official journal of the American Association for Cancer Research 2002 May;8(5):1057-64