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(ubiquitin / ubiquitin-ligases / cancer / cell cycle)
* Department of Pathology and Kaplan Comprehensive Cancer Center,
New York University School of Medicine, 550 First Avenue, MSB 548, New York, NY 10016; and Edited by Joan V. Ruderman, Harvard Medical School, Boston, MA,
and approved December 13, 2000 (received for review October 6, 2000)
The F-box protein Skp2 (S-phase kinase-associated
protein 2) positively regulates the G1-S transition by
controlling the stability of several G1 regulators, such as
the cell cycle inhibitor p27. We show here that Skp2 expression
correlates directly with grade of malignancy and inversely with p27
levels in human lymphomas. To directly evaluate the potential of Skp2
to deregulate growth in vivo, we generated transgenic
mice expressing Skp2 targeted to the T-lymphoid lineage as well as
double transgenic mice coexpressing Skp2 and activated N-Ras. A strong
cooperative effect between these two transgenes induced T cell
lymphomas with shorter latency and higher penetrance, leading to
significantly decreased survival when compared with control and single
transgenic animals. Furthermore, lymphomas of Nras
single transgenic 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.
Genetics
Role of the F-box protein Skp2 in lymphomagenesis
,,
Memorial Sloan-Kettering
Cancer Center, New York, NY 10021
To whom reprint requests should be addressed.
E-mail: paganm02{at}med.nyu.edu.
www.pnas.org/cgi/doi/10.1073/pnas.041475098
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