The apoptotic v-cyclin-CDK6 complex phosphorylates and inactivates Bcl-2

v-cyclin encoded by Kaposi's sarcoma herpesvirus/human herpesvirus 8 (KSHV or HHV8) associates with cellular cyclin-dependent kinase 6 (CDK6) to form a kinase complex that promotes cell-cycle progression, but can also induce apoptosis in cells with high levels of CDK6. Here we show that whereas HHV8 -encoded v-Bcl-5 protects against this apoptosis, cellular Bcl-2 has lost i ts anti-apoptotic potential as a result of an inactivating phosphorylation in its unstructured loop region. Moreover, we identify Bcl-2 as a new subst rate for v-cyclin-CDK6 in vitro, and show that it is present in a complex w ith CDK6 in cell lysates, A Bcl-2 mutant with a S70A S87A double substituti on in the loop region is not phosphorylated and provides resistance to apop tosis, indicating that inactivation of Bcl-2 by v-cyclin-CDK6 may be requir ed for the observed apoptosis. Furthermore, the identification of phosphory lated Bcl-2 in HHV8-positive Kaposi's sarcoma indicates that HHV8-mediated interference with host apoptotic signalling pathways may encourage the deve lopment of Kaposi's sarcoma.