Kaposi's sarcoma-associated herpesvirus-encoded v-cyclin triggers apoptosis in cells with high levels of cyclin-dependent kinase 6

Kaposi's sarcoma-associated herpesvirus (KSHV) has a key etiological role i n development of Kaposi's sarcoma (KS). v-Cyclin is a KSHV-encoded homologu e to D-type cyclins that associates with cellular cyclin-dependent kinase 6 (CDK6). v-Cyclin promotes S-phase entry of quiescent cells and has been su ggested to execute functions of both D- and E-type cyclins. In this study, expression of v-cyclin in cells with elevated levels of CDK6 led to apoptot ic cell death after the cells entered S phase. The cell death required the kinase activity of CDK6 because cells expressing a kinase-deficient form of CDK6 did not undergo apoptosis upon v-cyclin expression, Studies on the me chanisms involved in this caspase-3-mediated apoptosis indicated that it wa s independent of cellular p53 or pRb status, and it was not suppressed by B cl-2. In contrast, the KSHV-encoded v-Bcl-2 efficiently suppressed v-cyclin -/CDK6-induced apoptosis, demonstrating a marked difference in the antiapop totic properties of c-Bcl-2 and v-Bcl-2. In KS lesions, high CDK6 expressio n was confined to a subset of cells, some of which displayed signs of apopt osis. These results suggest that v-cyclin may exert both growth-promoting a nd apoptotic functions in KS, depending on factors regulating CDK6 and v-Bc l-2 levels.