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

Reduced levels of the cyclin-dependent kinase inhibitor p27Kip1 connote poor prognosis in cancer. In human Burkitt lymphoma and in precancerous B cells and lym-phomas arising in El-Myc transgenic mice, p27Kip1 expres-sion is markedly reduced. We show that the transcription of the Cks1 component of the SCFSkp2 complex that is necessary for p27Kip1 ubiquitylation and degradation is induced by Myc. Further, Cks1 expression is elevated in precancerous El-Myc B cells, and high levels of Cks1 are also a hallmark of El-Myc lymphoma and of human Burkitt lymphoma. Finally, loss of Cks1 in El-Myc B cells elevates p27Kip1 levels, reduces proliferation and markedly delays lymphoma development and dissemination of dis-ease. Therefore, Myc suppresses p27Kip1 expression, accel-erates cell proliferation and promotes tumorigenesis at least in part through its ability to selectively induce Cks1