|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 277, Issue 46, 44376-44384, November 15, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the 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.
Retinoblastoma Tumor Suppressor Targets dNTP Metabolism to
Regulate DNA Replication*
§,,,,
, and**
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 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.
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.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Derenzini, G. Donati, G. Mazzini, L. Montanaro, M. Vici, C. Ceccarelli, D. Santini, M. Taffurelli, and D. Trere Loss of Retinoblastoma Tumor Suppressor Protein Makes Human Breast Cancer Cells More Sensitive to Antimetabolite Exposure Clin. Cancer Res., April 1, 2008; 14(7): 2199 - 2209. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Gunawardena, S. R. Fox, H. Siddiqui, and E. S. Knudsen SWI/SNF Activity Is Required for the Repression of Deoxyribonucleotide Triphosphate Metabolic Enzymes via the Recruitment of mSin3B J. Biol. Chem., July 13, 2007; 282(28): 20116 - 20123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Takahashi, K. Kontani, Y. Araki, and T. Katada Caf1 regulates translocation of ribonucleotide reductase by releasing nucleoplasmic Spd1-Suc22 assembly Nucleic Acids Res., February 28, 2007; 35(4): 1187 - 1197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xue, B. Zhou, X. Liu, Y. Heung, J. Chau, E. Chu, S. Li, C. Jiang, F. Un, and Y. Yen Ribonucleotide Reductase Small Subunit p53R2 Facilitates p21 Induction of G1 Arrest under UV Irradiation Cancer Res., January 1, 2007; 67(1): 16 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. K. Mathews DNA precursor metabolism and genomic stability FASEB J, July 1, 2006; 20(9): 1300 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Knudsen and K. E. Knudsen Retinoblastoma tumor suppressor: where cancer meets the cell cycle. Experimental Biology and Medicine, July 1, 2006; 231(7): 1271 - 1281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. K. Jamburuthugoda, P. Chugh, and B. Kim Modification of Human Immunodeficiency Virus Type 1 Reverse Transcriptase to Target Cells with Elevated Cellular dNTP Concentrations J. Biol. Chem., May 12, 2006; 281(19): 13388 - 13395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Berthet, K. Raj, P. Saudan, and P. Beard How adeno-associated virus Rep78 protein arrests cells completely in S phase PNAS, September 20, 2005; 102(38): 13634 - 13639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Wang, C. J. Li, P. V. Reddy, and A. B. Pardee Cancer Chemotherapy by Deoxynucleotide Depletion and E2F-1 Elevation Cancer Res., September 1, 2005; 65(17): 7809 - 7814. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Holmberg, O. Fleck, H. A. Hansen, C. Liu, R. Slaaby, A. M. Carr, and O. Nielsen Ddb1 controls genome stability and meiosis in fission yeast Genes & Dev., April 1, 2005; 19(7): 853 - 862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Diamond, M. Roshal, V. K. Jamburuthugoda, H. M. Reynolds, A. R. Merriam, K. Y. Lee, M. Balakrishnan, R. A. Bambara, V. Planelles, S. Dewhurst, et al. Macrophage Tropism of HIV-1 Depends on Efficient Cellular dNTP Utilization by Reverse Transcriptase J. Biol. Chem., December 3, 2004; 279(49): 51545 - 51553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Gardner, F. Li, X. Yang, and C. V. Dang Anoxic Fibroblasts Activate a Replication Checkpoint That Is Bypassed By E1a Mol. Cell. Biol., December 15, 2003; 23(24): 9032 - 9045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Angus, D. A. Solomon, L. Kuschel, R. F. Hennigan, and E. S. Knudsen Retinoblastoma Tumor Suppressor: Analyses of Dynamic Behavior in Living Cells Reveal Multiple Modes of Regulation Mol. Cell. Biol., November 15, 2003; 23(22): 8172 - 8188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yen Ribonucleotide Reductase Subunit One as Gene Therapy Target: Commentary re: M-Y. Cao et al., Adenovirus-mediated Ribonucleotide Reductase R1 Gene Therapy of Human Colon Adenocarcinoma. Clin. Cancer Res., 9: 4304-4308, 2003. Clin. Cancer Res., October 1, 2003; 9(12): 4304 - 4308. [Full Text] [PDF]
|
|
|
|
|
|
J. Murren, M. Modiano, C. Clairmont, P. Lambert, N. Savaraj, T. Doyle, and M. Sznol Phase I and Pharmacokinetic Study of Triapine, a Potent Ribonucleotide Reductase Inhibitor, Administered Daily for Five Days in Patients with Advanced Solid Tumors Clin. Cancer Res., September 15, 2003; 9(11): 4092 - 4100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Lee, A. Vassilakos, N. Feng, V. Lam, H. Xie, M. Wang, H. Jin, K. Xiong, C. Liu, J. Wright, et al. GTI-2040, an Antisense Agent Targeting the Small Subunit Component (R2) of Human Ribonucleotide Reductase, Shows Potent Antitumor Activity against a Variety of Tumors Cancer Res., June 1, 2003; 63(11): 2802 - 2811. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |