Chk2 is dispensable for p53-mediated G1 arrest but is required for a latent p53-mediated apoptotic response.
In response to genotoxic stress, mammalian cells can activate cell cycle checkpoint pathways to arrest the cell for repair of DNA damage or induce apoptosis to eliminate damaged cells. The checkpoint kinase, Chk2, has been implicated in both of these responses and is believed to function in an ataxia telangiectasia (Atm)-dependent manner. We show here that Chk2-/- mouse embryo fibroblasts (MEFs), unlike Atm-/- or p53-/- MEFs, behaved like normal MEFs in manifesting p21 induction and G(1) arrest upon exposure to gamma-irradiation. Therefore, Chk2 is not involved in p53-mediated G(1) arrest. To examine the role of Chk2 in p53-dependent apoptotic response, we used adenovirus E1A-expressing MEFs. We show that Chk2-/- cells, like p53-/- cells, did not undergo DNA damage-induced apoptosis, whereas Atm-/- cells behaved like normal cells in invoking an apoptotic response. Furthermore, this apoptosis could occur in the absence of protein synthesis, suggesting that it is preexisting, or "latent," p53 that mediates this response. We conclude that Chk2 is not involved in Atm- and p53-dependent G(1) arrest, but is involved in the activation of latent p53, independently of Atm, in triggering DNA damage-induced apoptosis.
Jack
Melissa T
MT
Cancer Biology Research Group and Department of Microbiology and Infectious Diseases, University of Calgary Health Sciences Center, Calgary, AL, Canada T2N 4N1.
Woo
Richard A
RA
Hirao
Atsushi
A
Cheung
Alison
A
Mak
Tak W
TW
Lee
Patrick W K
PW
D000256:Adenoviridae / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016193:G1 Phase; D018014:Gene Transfer Techniques; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases