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Molecular and Cellular Biology, February 2006, p. 1170-1182, Vol. 26, No. 4
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.4.1170-1182.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Retinoblastoma Protein Is Required for Ras-Induced Oncogenic Transformation{dagger}

Jonathan P. Williams,1 Timothy Stewart,1 Bihua Li,1 Roseann Mulloy,1 Dessislava Dimova,2 and Marie Classon1*

MGH Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129,1 Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 088542

Received 4 April 2005/ Returned for modification 23 May 2005/ Accepted 20 October 2005

Most human cancers involve either mutational activation of the Ras oncogenic pathway and/or inactivation of the retinoblastoma tumor suppressor (RB) pathway. Paradoxically, tumors that harbor Ras mutations almost invariably retain expression of a wild-type pRB protein. We explain this phenomenon by demonstrating that Ras-induced oncogenic transformation surprisingly depends on functional pRB protein. Cells lacking pRB are less susceptible to the oncogenic actions of H-RasV12 than wild-type cells and activated Ras has an inhibitory effect on the proliferation of pRB-deficient human tumor cells. In addition, depletion of pRB from Ras-transformed murine cells or human tumor cells that harbor Ras pathway mutations inhibits their proliferation and anchorage-independent growth. In sharp contrast to pRB–/– 3T3 cells, fibroblasts deficient in other pRB family members (p107 and p130) are more susceptible to Ras-mediated transformation than wild-type 3T3 cells. Moreover, loss of pRB in tumor cells harboring a Ras mutation results in increased expression of p107, and overexpression of p107 but not pRB strongly inhibits proliferation of these tumor cells. Together, these findings suggest that pRB and p107 have distinct roles in Ras-mediated transformation and suggest a novel tumor-suppressive role for p107 in the context of activated Ras.

* Corresponding author. Mailing address: MGH Cancer Center and Harvard Medical School, Bldg. 149, 13th St., Charlestown, MA 02129. Phone: (617) 726-7804. Fax: (617) 726-7808. E-mail: classon{at}helix.mgh.harvard.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2006, p. 1170-1182, Vol. 26, No. 4
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.4.1170-1182.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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