Down-regulation of cell cycle control genes by ionizing radiation.
The cellular responses to ionizing radiation include growth arrest, DNA repair, and lethality. However, little is known about the signaling events responsible for these responses. The present studies have examined the effects of ionizing radiation on the expression of genes involved in cell cycle control. The results demonstrate that the treatment of asynchronous cells with 20 Gy ionizing radiation is associated with transient down-regulation of the cdc2, cyclin A, cyclin B, and cdc25 genes. This effect was associated with transient induction of the c-jun gene. RNA stability studies demonstrate that the down-regulation of gene expression following ionizing radiation exposure is at least in part due to a decrease in transcript half-life. Other studies were performed with elutriated cells enriched for populations in G1 and S phases. Treatment of G1 enriched cell populations with 10 Gy resulted in a selective decrease in cyclin B mRNA levels, whereas this effect on cyclin B expression was less pronounced at 5 Gy and undetectable at 1 Gy. Similar results were obtained with S phase enriched cells. Taken together with clonogenic survival studies, these findings indicate that down-regulation of cell cycle control gene expression is associated with lethality, whereas lower doses of ionizing radiation have little, if any, effect on the expression of these genes. The findings also suggest that DNA damage may activate signaling events which regulate expression of cell cycle control genes.
Datta
R
R
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Hass
R
R
Gunji
H
H
Weichselbaum
R
R
Kufe
D
D
D016203:CDC2 Protein Kinase / Q000235:genetics*; D002453:Cell Cycle / Q000528:radiation effects*; D016213:Cyclins / Q000235:genetics*; D015870:Gene Expression / Q000528:radiation effects; D006801:Humans; D066298:In Vitro Techniques; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014965:X-Rays; D020687:cdc25 Phosphatases
D016213:Cyclins; D011506:Proteins; D012333:RNA, Messenger; D016203:CDC2 Protein Kinase; D020687:cdc25 Phosphatases