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Originally published In Press as doi:10.1074/jbc.M205911200 on September 6, 2002

J. Biol. Chem., Vol. 277, Issue 46, 44376-44384, November 15, 2002
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Retinoblastoma Tumor Suppressor Targets dNTP Metabolism to Regulate DNA Replication*

Steven P. AngusDagger §, Linda J. Wheeler, Sejal A. RanmalDagger , Xiaoping ZhangDagger , Michael P. MarkeyDagger , Christopher K. Mathews||, and Erik S. KnudsenDagger **

From the Dagger  Department of Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267-0521 and  Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, 97331-7305

The retinoblastoma tumor suppressor, RB, is a negative regulator of the cell cycle that is inactivated in the majority of human tumors. Cell cycle inhibition elicited by RB has been attributed to the attenuation of CDK2 activity. Although ectopic cyclins partially overcome RB-mediated S-phase arrest at the replication fork, DNA replication remains inhibited and cells fail to progress to G2 phase. These data suggest that RB regulates an additional execution point in S phase. We observed that constitutively active RB attenuates the expression of specific dNTP synthetic enzymes: dihydrofolate reductase, ribonucleotide reductase (RNR) subunits R1/R2, and thymidylate synthase (TS). Activation of endogenous RB and related proteins by p16ink4a yielded similar effects on enzyme expression. Conversely, targeted disruption of RB resulted in increased metabolic protein levels (dihydrofolate reductase, TS, RNR-R2) and conferred resistance to the effect of TS or RNR inhibitors that diminish available dNTPs. Analysis of dNTP pools during RB-mediated cell cycle arrest revealed significant depletion, concurrent with the loss of TS and RNR protein. Importantly, the effect of active RB on cell cycle position and available dNTPs was comparable to that observed with specific antimetabolites. Together, these results show that RB-mediated transcriptional repression attenuates available dNTP pools to control S-phase progression. Thus, RB employs both canonical cyclin-dependent kinase/cyclin regulation and metabolic regulation as a means to limit proliferation, underscoring its potency in tumor suppression.


* The costs of publication of this article were defrayed in part by the payment of page charges. The 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. Tel.: 513-558-1086; Fax: 513-558-2445; E-mail: Steven.Angus@uc.edu.

|| Supported by National Institutes of Health Grant GM55134 and the National Science Foundation Grant MCB 9916576.

** Supported by the National Institutes of Health/National Cancer Institute Grant CA82525 and American Cancer Society Grant RSG-01-254-01-CCG.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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