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

Reduced levels of the cyclin- dependent kinase inhibitor p27(Kip1) connote poor prognosis in cancer. In human Burkitt lymphoma and in precancerous B cells and lymphomas arising in E mu- Myc transgenic mice, p27(Kip1) 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 E mu- Myc B cells, and high levels of Cks1 are also a hallmark of E mu- Myc lymphoma and of human Burkitt lymphoma. Finally, loss of Cks1 in E mu- Myc B cells elevates p27(Kip1) levels, reduces proliferation and markedly delays lymphoma development and dissemination of disease. Therefore, Myc suppresses p27(Kip1) expression, accelerates cell proliferation and promotes tumorigenesis at least in part through its ability to selectively induce Cks1.