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. , 
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. , , 
JNK and p38
alpha activate transcription of
c-Jun, which, in turn, excites
transcription of cyclin-dependent kinase 1 (CDK1).  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. 
Moreover, JNK stimulates activity of proapoptotic proteins,
Bcl-2 modifying factor (BMF) and BCL2-like 11 factor
JNK phosphorylates 14-3-3
protein, type 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
Activated c-Alb participates in apoptotic
pathways (e.g. via phosphorylation tumor p53-related protein
(p73) , transcription factor
c-Jun or apoptosis-related cysteine protease
9 (Caspase-9). 
In addition, c-Alb activates
protein kinase C, delta (PKC
delta).  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
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.  c-Abl neutralizes the inhibitory effect of
Mdm2 on p53. ,  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.  p53 may be activated by
component of Brca1/BARD1
complex, BARD1 too. 
Activated p53 regulates
transcription of apoptosis regulator Bax
, apoptotic protease activating factor
(Apaf-1)  and
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).
- 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
- Norbury CJ, Zhivotovsky B
DNA damage-induced apoptosis.
Oncogene 2004 Apr 12;23(16):2797-808
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Weller M
Predicting response to cancer chemotherapy: the role of p53.
Cell and tissue research 1998 Jun;292(3):435-45