Kaposi sarcoma-associated viral cyclin K overrides cell growth inhibition mediated by oncostatin M through STAT3 inhibition.
DNA viruses have evolved a number of mechanisms to inhibit the major cellular tumor-suppressor pathways. Viral oncogenes can override growth suppressive signals and extend the virus proliferative capacity. The Kaposi sarcoma-associated human herpesvirus 8 (KSHV) encodes a protein, cyclin K, that is similar to cellular cyclin D1 but behaves atypically. Cyclin K resists the actions of the p16 INK4a and p27Kip1 inhibitors and extends the range of cdk6 substrates, thereby inducing cell-cycle progression toward S phase. In this study, we show that cyclin K overrides growth suppressive signals through signal transducer and activator of transcription 3 (STAT3) inactivation. Cyclin K was found to associate with the activation domain of STAT3 to inhibit its DNA-binding and transcriptional activities. Overexpression of cyclin K and inhibition of STAT3 prevents the growth suppressive effect imposed by the interleukin 6-type cytokine, oncostatin M. Altogether, these results suggest that KSHV is able to override growth suppressive effects through multiple mechanisms, and they further indicate that cyclin K plays an important role in the oncogenic activity of these viruses.
Lundquist
Amy
A
Institut National de la Santé et de la Recherche Médicale U564, Angers, France.
Barré
Benjamin
B
Bienvenu
Frédéric
F
Hermann
Jacques
J
Avril
Sylvie
S
Coqueret
Olivier
O
D002455:Cell Division / Q000187:drug effects; D016213:Cyclins / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D006131:Growth Inhibitors / Q000494:pharmacology*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D008545:Melanoma; D053683:Oncostatin M; D010455:Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D012514:Sarcoma, Kaposi / Q000473:pathology / Q000821:virology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000494:pharmacology*
D016213:Cyclins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C508351:OSM protein, human; D010455:Peptides; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014764:Viral Proteins; D053683:Oncostatin M