Submitted July 5, 2002
Accepted December 30, 2002
Kaposi's sarcoma-associated viral cyclin K overrides cell growth inhibition mediated by oncostatin M through STAT3 inhibition
Amy Lundquist, Benjamin Barre, Frederic Bienvenu, Jacques Hermann, Sylvie Avril, and Olivier Coqueret*
INSERM, Unite 564, Angers, France
* Corresponding author; email: olivier.coqueret{at}univ-angers.fr.
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's sarsoma-associated human herpesvirus 8 (KSHV/HHV8) 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 towards S phase. In this study, we show that cyclin K overrides growth suppressive signals through 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 interleukine 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 play an important role in the oncogenic activity of these viruses.
