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Molecular and Cellular Biology, June 2002, p. 4309-4318, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4309-4318.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The RASSF1A Tumor Suppressor Blocks Cell Cycle Progression and Inhibits Cyclin D1 Accumulation

Latha Shivakumar,1 John Minna,2 Toshiyuki Sakamaki,3 Richard Pestell,3 and Michael A. White1*

Department of Cell Biology,1 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas 75390-9039,2 Division of Hormone-Dependent Tumor Biology, The Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 104613

Received 12 December 2001/ Returned for modification 23 January 2002/ Accepted 22 March 2002

The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G1/S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G1/S-phase cell cycle progression.

* Corresponding author. Mailing address: Department of Cell Biology UT Southwestern Medical Center, Dallas, TX 75390-9039. Phone: (214) 648-2861. Fax: (214) 648-8694. E-mail: michael.white{at}UTSouthwestern.edu.

Molecular and Cellular Biology, June 2002, p. 4309-4318, Vol. 22, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.12.4309-4318.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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