Kaposi sarcoma-associated viral cyclin K overrides cell growth inhibition mediated by oncostatin M through STAT3 inhibition

Blood. 2003 May 15;101(10):4070-7. doi: 10.1182/blood-2002-07-1994. Epub 2003 Jan 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / drug effects
  • Cyclins / pharmacology*
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Growth Inhibitors / pharmacology*
  • Herpesvirus 8, Human / physiology*
  • Humans
  • Melanoma
  • Oncostatin M
  • Peptides / antagonists & inhibitors
  • Peptides / pharmacology*
  • Recombinant Fusion Proteins / isolation & purification
  • Recombinant Fusion Proteins / pharmacology
  • STAT3 Transcription Factor
  • Sarcoma, Kaposi / pathology
  • Sarcoma, Kaposi / virology*
  • Trans-Activators / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Viral Proteins / pharmacology*

Substances

  • Cyclins
  • DNA-Binding Proteins
  • Growth Inhibitors
  • OSM protein, human
  • Peptides
  • Recombinant Fusion Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Viral Proteins
  • Oncostatin M