Cell Growth & Differentiation, Vol 8, Issue 11 1161-1169, Copyright © 1997 by American Association of Cancer Research

ARTICLES

CDC2 is down-regulated by ionizing radiation in a p53-dependent manner

EI Azzam, SM de Toledo, MJ Pykett, H Nagasawa and JB Little
Laboratory of Radiobiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

The mammalian cellular response to ionizing radiation results in delays in progression through the cell cycle at several checkpoints and includes alterations in the activity of cyclin-dependent kinases. The product of the CDC2 gene is a key kinase involved in cell cycle progression. The signaling events that regulate its expression after exposure to DNA-damaging agents are not known. We show that cdc2 mRNA and protein are down-regulated after irradiation of normal human and mouse fibroblasts with doses as low as 0.5 Gy. This down-regulation is preceded by induction of p53 and p21Waf1 proteins. In human cells in which p53 was nonfunctional and in p53-/- or p21-/- mouse embryo fibroblasts, no effect of ionizing radiation on p34cdc2 expression levels was observed. These findings indicate that CDC2 down-regulation after irradiation is p53-dependent and involves the cyclin-dependent kinase inhibitor p21Waf1 as a negative factor in the control of CDC2 expression. Correspondence between the delay in initiation of DNA synthesis in irradiated cells and the down-regulation of CDC2 is described.

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