Journal of Biological Chemistry
Volume 272, Issue 46, 14 November 1997, Pages 29301-29308
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CELL BIOLOGY AND METABOLISM
Role of the Tuberous Sclerosis Gene-2 Product in Cell Cycle Control: LOSS OF THE TUBEROUS SCLEROSIS GENE-2 INDUCES QUIESCENT CELLS TO ENTER S PHASE*

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Tuberous sclerosis is an autosomal dominant disorder characterized by the development of benign growths in many tissues and organs. Linkage analysis revealed two disease-determining genes on chromosome 9 and chromosome 16. TheTSC2 gene on chromosome 16 encodes a 1784-amino acid tumor suppressor protein, tuberin, that functions as a GTPase-activating protein for Rap1, a member of the superfamily of Ras-related proteins. By immunoblot analyses, we found TSC2 expression to be high in G0 as well as in early small G1 cells. Analyses after different cell synchronization procedures revealed thatTSC2 mRNA and protein expression do not fluctuate throughout the cell cycle. Using inducible expression systems we further demonstrated that TSC2 expression is not affected by overexpression of the mitogenic transcription factor E2F-1 or c-Myc. Nevertheless, antisense inhibition of tuberin expression in logarithmically growing cells markedly decreased the percentage of cells in G1. Furthermore, we found that cells exposed toTSC2 antisense oligonucleotides did not undergo G0 arrest after serum withdrawal. Antisense inhibition ofTSC2 expression also induced quiescent G0-arrested fibroblasts to reenter the cell cycle. Our data show for the first time that the absence of tuberin can both induce cells to pass through the G1/S transition of the eukaryotic cell cycle and prevent them from entering a quiescent state. These results have clear implications for the tumor suppressor function ofTSC2. We further found that reentry into the cell cycle upon loss of TSC2 is dependent on the activity of the G1 cyclin-dependent kinases (CDKs), Cdk2 or Cdk4. Taken together with our finding that antisense inhibition ofTSC2 causes up-regulation of cyclin D1 expression, these results provide the first evidence for a connection between tuberin/Rap1 and the G1 CDK-dependent regulation of the transition from G0/G1 to S phase.

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*

This work was supported by the “Komission Onkologie,” by a Ph.D. fellowship of the Medical Faculty of the University of Vienna, and by the Austrian Fonds zur Förderung der Wissenschaftlichen Forschung.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.

Fellow of the Deutsche Forschungsgemeinschaft (Wi 1302/1-1). Present address: Dept. of Dermatology, University of Munich, 80333 Munich, Germany.