KSHV viral cyclin binds to p27KIP1 in primary effusion lymphomas

Abstract

Primary effusion lymphomas (PELs) represent a unique non-Hodgkin lymphoma that is consistently infected by Kaposi sarcoma herpesvirus (KSHV). PEL cells express high levels of the cell cycle inhibitor p27KIP1 and yet proliferate actively. KSHV genome encodes a viral cyclin homolog, v-cyclin, which has previously been implicated in down-regulation of p27KIP1 levels. To address how PEL cells can tolerate high p27KIP1 levels, we investigated functional interactions between v-cyclin and p27KIP1 using PEL-derived cell lines as a model system. Here we demonstrate that v-cyclin and p27KIP1 stably associate in PEL cells in vivo suggesting an attractive model by which p27KIP1 is inactivated in the actively proliferating PEL cells. Moreover, we show that v-cyclin and cyclin-dependent kinase 6 (CDK6) form an active kinase without p27KIP1 and that CDK6 is the in vivo catalytic subunit of v-cyclin in PEL cells. These findings suggest that KSHV may promote oncogenesis in PEL by expressing v-cyclin, which both overrides negative cell cycle controls present in the PEL precursor cells and induces a strong proliferative signal via CDK6 kinase activity. © 2004 by The American Society of Hematology.