The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest

Citation
S. Wang et al., The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest, P NAS US, 97(4), 2000, pp. 1584-1588
Citations number
39
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
00278424 → ACNP
Volume
97
Issue
4
Year of publication
2000
Pages
1584 - 1588
Database
ISI
SICI code
0027-8424(20000215)97:4<1584:TCSODP>2.0.ZU;2-2
Abstract
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 th e differential activation of pathways downstream of p53 are unclear. Here w e provide evidence that the catalytic subunit of DNA-dependent protein kina se (DNA-PKcs) serves as an upstream effector for p53 activation in response to IR, linking DNA damage to apoptosis, DNA-PKcs knockout (DNA-PKcs-/-) mi ce were exposed to whole-body IR, and the cell-cycle and apoptotic response s were examined in their thymuses. Our data show that IR induction of apopt osis and Bar expression, both mediated via p53, was significantly suppresse d in the thymocytes of DNA-PKcs-/- mice. In contrast, IR-induced cell-cycle arrest and p21 expression were normal. Thus, DNA-PKcs deficiency selective ly disrupts p53-dependent apoptosis but nor cell-cycle arrest. We also conf irmed previous findings that p21 induction was attenuated and cell-cycle ar rest was defective in the thymoctyes of whole body-irradiated Atm-/- mice, but the apoptotic response was unperturbed. Taken together, our results sup port a model in which the upstream effecters DNA-PKcs and Atm selectively a ctivate p53 to differentially regulate cell-cycle and apoptotic responses. Whereas Atm selects for cell-cycle arrest but not apoptosis, DNA-PKcs selec ts for apoptosis but not cell-cycle arrest.