The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest.
DNA damage induced by ionizing radiation (IR) activates p53, leading to the regulation of downstream pathways that control cell-cycle progression and apoptosis. However, the mechanisms for the IR-induced p53 activation and the differential activation of pathways downstream of p53 are unclear. Here we provide evidence that the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) serves as an upstream effector for p53 activation in response to IR, linking DNA damage to apoptosis. DNA-PKcs knockout (DNA-PKcs-/-) mice were exposed to whole-body IR, and the cell-cycle and apoptotic responses were examined in their thymuses. Our data show that IR induction of apoptosis and Bax expression, both mediated via p53, was significantly suppressed in the thymocytes of DNA-PKcs-/- mice. In contrast, IR-induced cell-cycle arrest and p21 expression were normal. Thus, DNA-PKcs deficiency selectively disrupts p53-dependent apoptosis but not cell-cycle arrest. We also confirmed previous findings that p21 induction was attenuated and cell-cycle arrest was defective in the thymoctyes of whole body-irradiated Atm-/- mice, but the apoptotic response was unperturbed. Taken together, our results support a model in which the upstream effectors DNA-PKcs and Atm selectively activate p53 to differentially regulate cell-cycle and apoptotic responses. Whereas Atm selects for cell-cycle arrest but not apoptosis, DNA-PKcs selects for apoptosis but not cell-cycle arrest.
Wang
S
S
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; and Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Guo
M
M
Ouyang
H
H
Li
X
X
Cordon-Cardo
C
C
Kurimasa
A
A
Chen
D J
DJ
Fuks
Z
Z
Ling
C C
CC
Li
G C
GC
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D001260:Ataxia Telangiectasia / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics* / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D005434:Flow Cytometry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D013950:Thymus Gland / Q000473:pathology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014916:Whole-Body Irradiation; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases