Retinoblastoma Tumor Suppressor Targets dNTP Metabolism to Regulate DNA Replication
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...
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Published in | The Journal of biological chemistry Vol. 277; no. 46; pp. 44376 - 44384 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
15.11.2002
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Subjects | |
Online Access | Get full text |
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Summary: | 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 G 2 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M205911200 |