Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis

Abstract

Reduced levels of the cyclin-dependent kinase inhibitor p27Kip1 connote poor prognosis in cancer. In human Burkitt lymphoma and in precancerous B cells and lymphomas arising in Eμ-Myc transgenic mice, p27Kip1 expression is markedly reduced. We show that the transcription of the Cks1 component of the SCFSkp2 complex that is necessary for p27 Kip1 ubiquitylation and degradation is induced by Myc. Further, Cks1 expression is elevated in precancerous Eμ-Myc B cells, and high levels of Cks1 are also a hallmark of Eμ-Myc lymphoma and of human Burkitt lymphoma. Finally, loss of Cks1 in Eμ-Myc B cells elevates p27Kip1 levels, reduces proliferation and markedly delays lymphoma development and dissemination of disease. Therefore, Myc suppresses p27Kip1 expression, accelerates cell proliferation and promotes tumorigenesis at least in part through its ability to selectively induce Cks1. © 2007 European Molecular Biology Organization | All Rights Reserved.