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J. Biol. Chem., Vol. 279, Issue 42, 43667-43674, October 15, 2004

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Repression of G₀/G₁ Traverse in Human Fibroblasts Exposed to Low Levels of Ionizing Radiation^*

Walker Wharton

From the Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131

Quiescent cultures of human fibroblasts were exposed to levels of ionizing radiation sufficient to induce a transient growth delay, while causing only small decreases in long term clonogenicity. Following the mitogenic stimulation of damaged cells, cyclin D-associated kinase activity was induced to levels equivalent to those seen in control cultures. In addition, late G₀/G₁ E2F-dependent transcriptional and translational activity was observed in restimulated irradiated cells. However, cells became arrested prior to entry into S phase in a manner that paralleled the repression of cdk2-associated kinase activity. Cyclin A/cdk2-associated kinase activity was repressed in a biphasic manner following the irradiation of logarithmically growing cells. The initial rapid decline in activity to levels 50% of those observed in control cultures occurred prior to increases in cellular levels of p21^Cip1 protein, was not blocked by the addition of cycloheximide, and was not accompanied by alterations in cdk2 phosphotyrosine content. The subsequent repression to undetectable levels was coincident with the induction of p21^Cip1 and was dependent on de novo protein synthesis. Only a subpopulation of cyclin A complexes were associated with p21^Cip1 regardless of the magnitude of the repression of catalytic activity, although all cyclin A-cdk2-p21^Cip1 complexes were inactive. These data suggest that temporally and functionally distinct mechanisms mediate the repression of cyclin-cdk activity in damaged cells. In addition, we present evidence that irradiated cells are competent to traverse S phase and arrest in G₂ in the complete absence of cdk2-associated kinase activity.

Received for publication, July 14, 2004 , and in revised form, August 9, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Internal Medicine, MSC10 5550, University of New Mexico Health Sciences Center, Albuquerque, NM 87131. Tel.: 505-272-9897; Fax: 505-272-9912; E-mail: wwharton{at}salud.unm.edu.

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