May 2008

A breakthrough in the understanding of the pathogenesis of the Karposi Sarcoma Herpes Virus.

One of the pathogenic gene products of the Karposi Sarcoma Herpes Virus (KSHV) is the D-like K-cyclin, which constitutively activates the cellular protein kinase CDK6 that normally is tightly regulated by cyclin D. Emanuela Cuomo and Axel Knebel have carried out a KESTREL kinase substrate screen with CDK6 / K-cyclin and identified NPM1 (B23 nucleophosmin) as a physiological substrate. In collaboration with Nick Morrice at the MRC Protein Phosphorylation Unit, University of Dundee Emanuela mapped Thr219 and more importantly Thr199 of NPM1 as the phosphorylation sites. In a normal cell cycle CDK2 phosphorylates NPM1 and mediates centrosome duplication. However, when cells are infected with KSHV then CDK6 / K-cyclin promote via NPM1 phosphorylation untimely centrosome duplication. The tumor suppressor p53 plays a critical role in mediating the elimination of supernucleated cells through apoptosis, so that cells with centrosome duplications can be found, but not polyploid cells.

(Cuomo et al., May 2008 Nat Cell Biol. in press).