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 in development of Kaposi's sarcoma (KS). v-Cyclin is a KSHV-encoded homologue 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 suggested 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 apoptotic 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 mechanisms involved in this caspase-3-mediated apoptosis indicated that it was independent of cellular p53 or pRb status, and it was not suppressed by Bcl-2. In contrast, the KSHV-encoded v-Bcl-2 efficiently suppressed v-cyclin-/CDK6-induced apoptosis, demonstrating a marked difference in the antiapoptotic properties of c-Bcl-2 and v-Bcl-2. In KS lesions, high CDK6 expression was confined to a subset of cells, some of which displayed signs of apoptosis. These results suggest that v-cyclin may exert both growth-promoting and apoptotic functions in KS, depending on factors regulating CDK6 and v-Bcl-2 levels.
Ojala
P M
PM
Cell Cycle Laboratory, Haartman Institute, University of Helsinki, Finland. Paivi.Ojala@helsinki.fi
Tiainen
M
M
Salven
P
P
Veikkola
T
T
Castaños-Vélez
E
E
Sarid
R
R
Biberfeld
P
P
Mäkelä
T P
TP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001859:Bone Neoplasms; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D012516:Osteosarcoma; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000201:enzymology / Q000473:pathology*; D019311:Staurosporine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014764:Viral Proteins
D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D014764:Viral Proteins; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D017346:Protein Serine-Threonine Kinases; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine