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Molecular and Cellular Biology, June 2006, p. 4701-4711, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.00303-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulation of Late G1/S Phase Transition and APCCdh1 by Reactive Oxygen Species{dagger}

Courtney G. Havens, Alan Ho,{ddagger} Naohisa Yoshioka, and Steven F. Dowdy*

Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California—San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0686

Received 17 February 2006/ Returned for modification 14 March 2006/ Accepted 29 March 2006

Proliferating cells have a higher metabolic rate than quiescent cells. To investigate the role of metabolism in cell cycle progression, we examined cell size, mitochondrial mass, and reactive oxygen species (ROS) levels in highly synchronized cell populations progressing from early G1 to S phase. We found that ROS steadily increased, compared to cell size and mitochondrial mass, through the cell cycle. Since ROS has been shown to influence cell proliferation and transformation, we hypothesized that ROS could contribute to cell cycle progression. Antioxidant treatment of cells induced a late-G1-phase cell cycle arrest characterized by continued cellular growth, active cyclin D-Cdk4/6 and active cyclin E-Cdk2 kinases, and inactive hyperphosphorylated pRb. However, antioxidant-treated cells failed to accumulate cyclin A protein, a requisite step for initiation of DNA synthesis. Further examination revealed that cyclin A continued to be ubiquitinated by the anaphase promoting complex (APC) and to be degraded by the proteasome. This antioxidant arrest could be rescued by overexpression of Emi1, an APC inhibitor. These observations reveal an intrinsic late-G1-phase checkpoint, after transition across the growth factor-dependent G1 restriction point, that links increased steady-state levels of endogenous ROS and cell cycle progression through continued activity of APC in association with Cdh1.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California—San Diego, School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0686. Phone: (858) 534-7772. Fax: (858) 534-7797. E-mail: sdowdy{at}ucsd.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present addresses: Weill Medical College of Cornell, New York, N.Y.

Molecular and Cellular Biology, June 2006, p. 4701-4711, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.00303-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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