CDC2 is down-regulated by ionizing radiation in a p53-dependent manner.
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.
Azzam
E I
EI
Laboratory of Radiobiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
de Toledo
S M
SM
Pykett
M J
MJ
Nagasawa
H
H
Little
J B
JB
D000818:Animals; D016203:CDC2 Protein Kinase / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000528:radiation effects; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase