KSHV viral cyclin binds to p27KIP1 in primary effusion lymphomas.
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 p27(KIP1) and yet proliferate actively. KSHV genome encodes a viral cyclin homolog, v-cyclin, which has previously been implicated in down-regulation of p27(KIP1) levels. To address how PEL cells can tolerate high p27(KIP1) levels, we investigated functional interactions between v-cyclin and p27(KIP1) using PEL-derived cell lines as a model system. Here we demonstrate that v-cyclin and p27(KIP1) stably associate in PEL cells in vivo suggesting an attractive model by which p27(KIP1) 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 p27(KIP1) 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.
Järviluoma
Annika
A
Molecular Cancer Biology Program, Biomedicum Helsinki & Haartman Institute, Helsinki, Finland.
Koopal
Sonja
S
Räsänen
Susanna
S
Mäkelä
Tomi P
TP
Ojala
Päivi M
PM
D002384:Catalysis; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D019288:Herpesvirus 8, Human; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000378:metabolism* / Q000821:virology; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000821:virology; D012516:Osteosarcoma; D011485:Protein Binding; D012514:Sarcoma, Kaposi / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins
D018797:Cell Cycle Proteins; D016213:Cyclins; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases