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Persistent Inhibition of DNA Synthesis in Irradiated Rat Embryo Fibroblasts Expressing the Oncogenes H-ras plus v-myc Derives from Inhibition of Replicon Initiation and Is Mitigated by Staurosporine¹

Thomas Jefferson University, Department of Radiation Oncology and Nuclear Medicine, Philadelphia, Pennsylvania 19107

We have previously shown that rat embryo fibroblasts expressing the oncogenes H-ras plus v-myc experience a prolonged inhibition of DNA replication after exposure to ionizing radiation as compared to normal rat embryo fibroblasts, or rat embryo fibroblasts expressing H-ras or v-myc alone. Here we show that this enhanced inhibition of DNA replication in cells expressing H-ras plus v-myc is due to inhibition of the main controlling event of DNA replication, i.e., replicon initiation, that this inhibition is reversible, and that the expression of this phenotype is reverted by staurosporine, a protein kinase inhibitor. These findings implicate genetic influences in the processes that control DNA replication in irradiated cells and identify events in the regulation of DNA replication that become apparent several hours after irradiation. The products of the oncogenes H-ras and v-myc appear to be members of, or exert influence on, this controlling pathway.

¹ Supported by National Cancer Institute Grants CA45557 and CA42026 awarded by the NIH, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Thomas Jefferson University, Department of Radiation Oncology and Nuclear Medicine, Thompson Building, Room B13, Philadelphia, PA 19107.

Received 11/13/92. Accepted 2/ 1/93.

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