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Molecular and Cellular Biology, May 2008, p. 3190-3197, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02291-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The RASSF1A Tumor Suppressor Restrains Anaphase-Promoting Complex/Cyclosome Activity during the G1/S Phase Transition To Promote Cell Cycle Progression in Human Epithelial Cells{triangledown}

Angelique W. Whitehurst,1 Rosalyn Ram,1 Latha Shivakumar,1 Boning Gao,2 John D. Minna,2 and Michael A. White1*

Department of Cell Biology,1 Hamon Cancer Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas 753902

Received 27 December 2007/ Returned for modification 29 January 2008/ Accepted 10 March 2008

Multiple molecular lesions in human cancers directly collaborate to deregulate proliferation and suppress apoptosis to promote tumorigenesis. The candidate tumor suppressor RASSF1A is commonly inactivated in a broad spectrum of human tumors and has been implicated as a pivotal gatekeeper of cell cycle progression. However, a mechanistic account of the role of RASSF1A gene inactivation in tumor initiation is lacking. Here we have employed loss-of-function analysis in human epithelial cells for a detailed investigation of the contribution of RASSF1 to cell cycle progression. We found that RASSF1A has dual opposing regulatory connections to G1/S phase cell cycle transit. RASSF1A associates with the Ewing sarcoma breakpoint protein, EWS, to limit accumulation of cyclin D1 and restrict exit from G1. Surprisingly, we found that RASSF1A is also required to restrict SCFβTrCP activity to allow G/S phase transition. This restriction is required for accumulation of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 and the concomitant block of APC/C-dependent cyclin A turnover. The consequence of this relationship is inhibition of cell cycle progression in normal epithelial cells upon RASSF1A depletion despite elevated cyclin D1 concentrations. Progression to tumorigenicity upon RASSF1A gene inactivation should therefore require collaborating genetic aberrations that bypass the consequences of impaired APC/C regulation at the G1/S phase cell cycle transition.

* Corresponding author. Mailing address: Department Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75220-9039. Phone: (214) 648-2861. Fax: (214) 648-8694. E-mail: michael.white{at}utsouthwestern.edu

{triangledown} Published ahead of print on 17 March 2008.

Molecular and Cellular Biology, May 2008, p. 3190-3197, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02291-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Macheiner, D., Gauglhofer, C., Rodgarkia-Dara, C., Grusch, M., Brachner, A., Bichler, C., Kandioler, D., Sutterluty, H., Mikulits, W., Schulte-Hermann, R., Grasl-Kraupp, B. (2009). NORE1B Is a Putative Tumor Suppressor in Hepatocarcinogenesis and May Act via RASSF1A. Cancer Res. 69: 235-242 [Abstract] [Full Text]  


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