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J. Biol. Chem., Vol. 278, Issue 21, 19358-19366, May 23, 2003

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Distinct Mechanisms for Regulating the Tumor Suppressor and Antiapoptotic Functions of Rb^*

Duanduan Ma , Ping Zhou  and J. William Harbour 

From the Departments of Ophthalmology and Visual Sciences and of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

The retinoblastoma protein, Rb, suppresses tumorigenesis by inhibiting cell proliferation and promoting senescence and differentiation. Paradoxically, Rb also inhibits apoptosis, which would seem to oppose its tumor suppressor function. Further, most human cancer cells inactivate Rb by hyperphosphorylation and demonstrate increased proliferative capacity but not high levels of apoptosis. As a potential explanation for these findings, we show here that the tumor suppressor and antiapoptotic functions of Rb are regulated by distinct phosphorylation events. Phosphorylation of sites in the C terminus occurs efficiently every cell cycle and regulates proliferation. Phosphorylation of Ser⁵⁶⁷ is inefficient and does not occur during the normal cell cycle. However, high cyclin-dependent kinase activity promotes phosphorylation of Ser⁵⁶⁷ by inducing an intramolecular interaction that leads to release of E2F, degradation of Rb, and susceptibility to apoptosis. Thus, phosphorylation of Ser⁵⁶⁷ may limit excessive proliferation by triggering cell death under hyperproliferative conditions. These findings suggest that the antiproliferative and antiapoptotic activities of Rb may represent complementary functions that work in concert to maintain the proliferation rate of cells within certain limits. As a survival strategy, some cancer cells may exploit this dual role of Rb by phosphorylating sites that regulate tumor suppression but avoiding phosphorylation of Ser⁵⁶⁷ and consequent apoptotic stimulus.

Received for publication, February 19, 2003 , and in revised form, March 19, 2003.

To whom correspondence should be addressed: Campus Box 8069, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-8989; Fax: 314-747-2797; E-mail: harbour{at}vision.wustl.edu.

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