Apoptosis and survival - p53-dependent apoptosis

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p53-dependent apoptosis

Direct DNA damage by ionizing radiation or UV can activates the interconnected apoptotic pathways by stimulation of protein kinases from phosphoinositide-3-kinases family. These stimulated kinases directly or indirectly activate phosphorylation of proteins from apoptotic pathways: tumor suppressor p53, breast and ovarian cancer susceptibility protein 1 (Brca1), E2F transcription factor 1 (E2F1), proto-oncogene tyrosine-protein kinase c-Abl and cell cycle regulator RAD9. [1], [2]

Stimulated Brca1 and p53 excite transcription of growth arrest and DNA-damage-inducible transcripts alpha and beta (GADD45 alpha/beta). GADD45alpha/beta triggers apoptosis through activation of mitogen-activated protein kinase kinase kinase 4 (MEKK4)/ mitogen-activated protein kinase kinase 4 (MKK4) or mitogen-activated protein kinase kinase 7 (MKK7)/ c-Jun N-terminal kinase/stress-activated protein kinase (JNK) cascade and/or MEKK4 / MKK4 or MKK7 / mitogen-activated protein kinase 14 (p38 alpha) cascade. [1], [3], [4]

JNK and p38 alpha activate transcription of c-Jun, which, in turn, excites transcription of cyclin-dependent kinase 1 (CDK1). [5] CDK1 catalyzes phosphorylation of the Bcl-2 - antagonist of cell death protein (BAD) at a distinct site, serine 128, and thereby induces BAD-mediated apoptosis. [6] Moreover, JNK stimulates activity of proapoptotic proteins, Bcl-2 modifying factor (BMF) and BCL2-like 11 factor (Bim). [7]

JNK phosphorylates 14-3-3 protein, type sigma (14-3-3 sigma) and stimulates the break of the links between 14-3-3 sigma and c-Alb and between 14-3-3 sigma and Bcl-2 - associated X protein (Bax), that result in activation c-Alb and Bax. Activated c-Alb participates in apoptotic pathways (e.g. via phosphorylation tumor p53-related protein (p73) [8], transcription factor c-Jun or apoptosis-related cysteine protease 9 (Caspase-9). [9]

In addition, c-Alb activates protein kinase C, delta (PKC delta). [10] PKC- delta and ATM may activate by phosphorylation RAD9. RAD9, BAD and BMF are bound with B-cell lymphoma protein 2 (Bcl-2) and inhibit its anti-apoptosis activity.

Nuclear protein p53 plays an important role in apoptosis. The basal p53-Mdm2 loop is an essential component of p53 regulation is. The ubiquitin-protein ligase E3 Mdm2 protein ubiquitinates and promotes degradation of p53. On the other hand, the mdm2 gene is the direct target for binding and transcriptional activation by p53. [11] c-Abl neutralizes the inhibitory effect of Mdm2 on p53. [12], [13] In addition, during indirect activation of p53, E2F1 excite the transcription of cyclin-dependent kinase inhibitor 2A (p14ARF), which interacts with Mdm2 and blocks the ability of Mdm2 to target p53 for destruction. [14] p53 may be activated by component of Brca1/BARD1 complex, BARD1 too. [15]

Activated p53 regulates transcription of apoptosis regulator Bax [16], apoptotic protease activating factor (Apaf-1) [17] and Bcl-2. [18]

E2F may activate apoptosis pathways by stimulation of p53 14-3-3 protein, type tau (14-3-3 tau) is required for expression and induction of E2F1 apoptotic targets, such as p73, Apaf-1, and apoptosis-related cysteine protease 3 (Caspase-3). {PMID: 15494392}

References:

  1. Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C, Christians FC, Ellisen LW, Maheswaran S, Oliner JD, Haber DA
    Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 1999 May 28;97(5):575-86
  2. Norbury CJ, Zhivotovsky B
    DNA damage-induced apoptosis. Oncogene 2004 Apr 12;23(16):2797-808
  3. Takekawa M, Saito H
    A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 1998 Nov 13;95(4):521-30
  4. Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S, Nguyen DU, Pham CG, Nelsbach AH, Melis T, De Smaele E, Tang WJ, D'Adamio L, Franzoso G
    Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. Nature cell biology 2004 Feb;6(2):146-53
  5. Wada T, Joza N, Cheng HY, Sasaki T, Kozieradzki I, Bachmaier K, Katada T, Schreiber M, Wagner EF, Nishina H, Penninger JM
    MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nature cell biology 2004 Mar;6(3):215-26
  6. Konishi Y, Lehtinen M, Donovan N, Bonni A
    Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Molecular cell 2002 May;9(5):1005-16
  7. Lei K, Davis RJ
    JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America 2003 Mar 4;100(5):2432-7
  8. Agami R, Blandino G, Oren M, Shaul Y
    Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 1999 Jun 24;399(6738):809-13
  9. Raina D, Pandey P, Ahmad R, Bharti A, Ren J, Kharbanda S, Weichselbaum R, Kufe D
    c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. The Journal of biological chemistry 2005 Mar 25;280(12):11147-51
  10. Sun X, Wu F, Datta R, Kharbanda S, Kufe D
    Interaction between protein kinase C delta and the c-Abl tyrosine kinase in the cellular response to oxidative stress. The Journal of biological chemistry 2000 Mar 17;275(11):7470-3
  11. Oren M, Damalas A, Gottlieb T, Michael D, Taplick J, Leal JF, Maya R, Moas M, Seger R, Taya Y, Ben-Ze'Ev A
    Regulation of p53: intricate loops and delicate balances. Annals of the New York Academy of Sciences 2002 Nov;973:374-83
  12. Sionov RV, Moallem E, Berger M, Kazaz A, Gerlitz O, Ben-Neriah Y, Oren M, Haupt Y
    c-Abl neutralizes the inhibitory effect of Mdm2 on p53. The Journal of biological chemistry 1999 Mar 26;274(13):8371-4
  13. Sionov RV, Coen S, Goldberg Z, Berger M, Bercovich B, Ben-Neriah Y, Ciechanover A, Haupt Y
    c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination. Molecular and cellular biology 2001 Sep;21(17):5869-78
  14. Lin WC, Lin FT, Nevins JR
    Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes & development 2001 Jul 15;15(14):1833-44
  15. Feki A, Jefford CE, Berardi P, Wu JY, Cartier L, Krause KH, Irminger-Finger I
    BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. Oncogene 2005 May 26;24(23):3726-36
  16. Lu J, Ho CH, Ghai G, Chen KY
    Resveratrol analog, 3,4,5,4'-tetrahydroxystilbene, differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts. Carcinogenesis 2001 Feb;22(2):321-8
  17. Moroni MC, Hickman ES, Lazzerini Denchi E, Caprara G, Colli E, Cecconi F, Müller H, Helin K
    Apaf-1 is a transcriptional target for E2F and p53. Nature cell biology 2001 Jun;3(6):552-8
  18. Weller M
    Predicting response to cancer chemotherapy: the role of p53. Cell and tissue research 1998 Jun;292(3):435-45

  1. Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C, Christians FC, Ellisen LW, Maheswaran S, Oliner JD, Haber DA
    Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 1999 May 28;97(5):575-86
  2. Norbury CJ, Zhivotovsky B
    DNA damage-induced apoptosis. Oncogene 2004 Apr 12;23(16):2797-808
  3. Takekawa M, Saito H
    A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 1998 Nov 13;95(4):521-30
  4. Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S, Nguyen DU, Pham CG, Nelsbach AH, Melis T, De Smaele E, Tang WJ, D'Adamio L, Franzoso G
    Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. Nature cell biology 2004 Feb;6(2):146-53
  5. Wada T, Joza N, Cheng HY, Sasaki T, Kozieradzki I, Bachmaier K, Katada T, Schreiber M, Wagner EF, Nishina H, Penninger JM
    MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nature cell biology 2004 Mar;6(3):215-26
  6. Konishi Y, Lehtinen M, Donovan N, Bonni A
    Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Molecular cell 2002 May;9(5):1005-16
  7. Lei K, Davis RJ
    JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America 2003 Mar 4;100(5):2432-7
  8. Agami R, Blandino G, Oren M, Shaul Y
    Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 1999 Jun 24;399(6738):809-13
  9. Raina D, Pandey P, Ahmad R, Bharti A, Ren J, Kharbanda S, Weichselbaum R, Kufe D
    c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. The Journal of biological chemistry 2005 Mar 25;280(12):11147-51
  10. Sun X, Wu F, Datta R, Kharbanda S, Kufe D
    Interaction between protein kinase C delta and the c-Abl tyrosine kinase in the cellular response to oxidative stress. The Journal of biological chemistry 2000 Mar 17;275(11):7470-3
  11. Oren M, Damalas A, Gottlieb T, Michael D, Taplick J, Leal JF, Maya R, Moas M, Seger R, Taya Y, Ben-Ze'Ev A
    Regulation of p53: intricate loops and delicate balances. Annals of the New York Academy of Sciences 2002 Nov;973:374-83
  12. Sionov RV, Moallem E, Berger M, Kazaz A, Gerlitz O, Ben-Neriah Y, Oren M, Haupt Y
    c-Abl neutralizes the inhibitory effect of Mdm2 on p53. The Journal of biological chemistry 1999 Mar 26;274(13):8371-4
  13. Sionov RV, Coen S, Goldberg Z, Berger M, Bercovich B, Ben-Neriah Y, Ciechanover A, Haupt Y
    c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination. Molecular and cellular biology 2001 Sep;21(17):5869-78
  14. Lin WC, Lin FT, Nevins JR
    Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes & development 2001 Jul 15;15(14):1833-44
  15. Feki A, Jefford CE, Berardi P, Wu JY, Cartier L, Krause KH, Irminger-Finger I
    BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. Oncogene 2005 May 26;24(23):3726-36
  16. Lu J, Ho CH, Ghai G, Chen KY
    Resveratrol analog, 3,4,5,4'-tetrahydroxystilbene, differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts. Carcinogenesis 2001 Feb;22(2):321-8
  17. Moroni MC, Hickman ES, Lazzerini Denchi E, Caprara G, Colli E, Cecconi F, Müller H, Helin K
    Apaf-1 is a transcriptional target for E2F and p53. Nature cell biology 2001 Jun;3(6):552-8
  18. Weller M
    Predicting response to cancer chemotherapy: the role of p53. Cell and tissue research 1998 Jun;292(3):435-45

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