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J. Biol. Chem., Vol. 281, Issue 46, 34759-34767, November 17, 2006

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Ras Triggers Ataxia-telangiectasia-mutated and Rad-3-related Activation and Apoptosis through Sustained Mitogenic Signaling^*

From the Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Genetic evidence indicates that Ras plays a critical role in the initiation and progression of human thyroid tumors. Paradoxically, acute expression of activated Ras in normal rat thyroid cells induced deregulated cell cycle progression and apoptosis. We investigated whether cell cycle progression was required for Ras-stimulated apoptosis. Ras increased CDK-2 activity following its introduction into quiescent cells. Apoptotic cells exhibited a sustained increase in CDK-2 activity, accompanied by the loss of CDK-2-associated p27. Blockade of Ras-induced CDK-2 activity and S phase entry via overexpression of p27 inhibited apoptosis. Inactivation of the retinoblastoma protein in quiescent cells through expression of HPV-E7 stimulated cell cycle progression and apoptosis, indicating that deregulated cell cycle progression is sufficient to induce apoptosis. Ras failed to induce G₁ phase growth arrest in normal rat thyroid cells. Rather, Ras-expressing thyroid cells progressed into S and G₂ phases and evoked a checkpoint response characterized by the activation of ATR. Ras-stimulated ATR activity, as evidenced by Chk1 and p53 phosphorylation, was blocked by p27, suggesting that cell cycle progression triggers checkpoint activation, likely as a consequence of replication stress. These data reveal that Ras is capable of inducing a DNA damage response with characteristics similar to those reported in precancerous lesions. Our findings also suggest that the frequent mutational activation of Ras in thyroid tumors reflects the ability of Ras-expressing cells to bypass checkpoints and evade apoptosis rather than to simply increase proliferative potential.

Received for publication, July 14, 2006 , and in revised form, August 24, 2006.

^* This work was supported by Public Health Service Grant DK55757 (to J. M.). 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.

¹ Present address: Institute for Anatomy and Cell Biology, Dept. of Biomedicine, University of Bergen, 5009 Bergen, Norway.

² To whom correspondence should be addressed: Dept. of Pharmacology, University of Pennsylvania School of Medicine, 421 Curie Blvd, 1251 BRB II/III, Philadelphia, PA 19104-6061. Tel.: 215-898-1909; Fax: 215-573-2236; E-mail: meinkoth{at}pharm.med.upenn.edu.

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