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
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.