Transcription - P53 signaling pathway

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p53 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 [1], [3]. 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 (New York, N.Y.) 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

  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 (New York, N.Y.) 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

Target Details

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