Apoptosis and survival - p53-dependent apoptosis

Click on a target from the pathway image to view related information. Zoom     View Legend

photo_map
 


Human PrimePCR Selections
photo_fpc
Apoptosis and survival-p53-dependent apoptosis H96

Predesigned 96-well panel for use with SYBR® Green

 

List Price:  $366.00

 

Your Price : Log In

photo_fpc
Apoptosis and survival-p53-dependent apoptosis H384

Predesigned 384-well panel for use with SYBR® Green

 

List Price:  $523.00

 

Your Price : Log In

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

Target Details

Click on a target from the pathway image to view related information.

[ Close ]
Click here to print
[ Close ]
Click here to print
 

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined