Role of the F-box protein Skp2 in lymphomagenesis

The F-box protein Skp2 (S-phase kinase-associated protein 2) positively reg ulates the G(1)-S transition by controlling the stability of several G(1) r egulators, such as the cell cycle inhibitor p27. We show here that Skp2 exp ression correlates directly with grade of malignancy and inversely with p27 levels in human lymphomas. To directly evaluate the potential of Skp2 to d eregulate growth in vivo, we generated transgenic mice expressing Skp2 targ eted to the T-lymphoid lineage as well as double transgenic mice coexpressi ng Skp2 and activated N-Ras. A strong cooperative effect between these two transgenes induced T cell lymphomas with shorter latency and higher penetra nce, leading to significantly decreased survival when compared with control and single transgenic animals. Furthermore, lymphomas of Nras single trans genic animals often expressed higher levels of endogenous Skp2 than tumors of double transgenic mice. This study provides evidence of a role for an F- box protein in oncogenesis and establishes SKP2 as a protooncogene causally involved in the pathogenesis of lymphomas.