The role of Ataxia telangiectasia and the DNA-dependent protein kinase in the p53-mediated cellular response to ionising radiation.
The DNA-dependent protein kinase (DNA-PK), whose catalytic subunit shows structural similarities to the Ataxia telangiectasia (AT) gene product (ATM), has also been implicated in the p53-mediated signal transduction pathway that activates the cellular response to DNA damage produced by ionizing radiation. DNA-PK activity however was not found to be related to the transcriptional induction of WAFl/CIP1(p2l) in AT lymphoblastoid cell lines, following treatment with ionizing radiation. Normal protein and transcription levels of Ku70 and Ku80, as well as DNA-PK activity, were found in six different AT cell lines, 1-4 h following exposure to ionizing radiation, timepoints where reduced and delayed transcriptional induction of WAF1/CIP1 (p21) was observed. WAF1/CIP1 (p21) was found to be transcriptionally induced by p53 in normal cell lines over this same time period following exposure to ionizing radiation. These results suggest that despite the findings that in vitro DNA-PK may phosphorylate p53, in vivo it would not appear to play a central role in the activation of p53 as a transcription factor nor can it substitute for the ATM gene product in the cellular response following exposure to ionizing radiation.
Jongmans
W
W
Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Artuso
M
M
Vuillaume
M
M
Brésil
H
H
Jackson
S P
SP
Hall
J
J
D000818:Animals; D034961:Antigens, Nuclear; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015152:Blotting, Northern; D002453:Cell Cycle / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism / Q000528:radiation effects*; D004249:DNA Damage; D004265:DNA Helicases; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen; D008221:Lymphoid Tissue / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D034961:Antigens, Nuclear; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen