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J. Biol. Chem., Vol. 281, Issue 7, 3800-3809, February 17, 2006

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Oncogenic RAS Induces Accelerated Transition through G₂/M and Promotes Defects in the G₂ DNA Damage and Mitotic Spindle Checkpoints^*

Jeffrey A. Knauf¹, Bin Ouyang¹, Erik S. Knudsen, Kenji Fukasawa, George Babcock^¶, and James A. Fagin²

From the Division of Endocrinology and Metabolism, the Department of Cell Biology, Neurobiology, and Anatomy, and the ^¶Division of Burn Surgery/Shriners Burns Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267

Activating mutations of RAS are prevalent in thyroid follicular neoplasms, which commonly have chromosomal losses and gains. In thyroid cells, acute expression of HRAS^V12 increases the frequency of chromosomal abnormalities within one or two cell cycles, suggesting that RAS oncoproteins may interfere with cell cycle checkpoints required for maintenance of a stable genome. To explore this, PCCL3 thyroid cells with conditional expression of HRAS^V12 or HRAS^V12 effector mutants were presynchronized at the G₁/S boundary, followed by activation of expression of RAS mutants and release from the cell cycle block. Expression of HRAS^V12 accelerated the G₂/M phase by 4 h and promoted bypass of the G₂ DNA damage and mitotic spindle checkpoints. Accelerated passage through G₂/M and bypass of the G₂ DNA damage checkpoint, but not bypass of the mitotic spindle checkpoint, required activation of mitogen-activated protein kinase (MAPK). However, selective activation of the MAPK pathway was not sufficient to disrupt the G₂ DNA damage checkpoint, because cells arrested appropriately in G₂ despite conditional expression of HRAS^V12,S35 or BRAF^V600E. By contrast to the MAPK requirement for radiation-induced G₂ arrest, RAS-induced bypass of the mitotic spindle checkpoint was not prevented by pretreatment with MEK inhibitors. These data support a direct role for the MAPK pathway in control of G₂ progression and regulation of the G₂ DNA damage checkpoint. We propose that oncogenic RAS activation may predispose cells to genomic instability through both MAPK-dependent and independent pathways that affect critical checkpoints in G₂/M.

Received for publication, October 28, 2005

^* This work was supported in part by National Institutes of Health Grant CA72597. 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Div. of Endocrinology and Metabolism, University of Cincinnati College of Medicine, 231 Bethesda Ave., Rm. 5564, Cincinnati, OH 45267-0547. E-mail: James.Fagin{at}uc.edu.

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