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 Emu-Myc transgenic mice, p27(Kip1) expression is markedly reduced. We show that the transcription of the Cks1 component of the SCF(Skp2) complex that is necessary for p27(Kip1) ubiquitylation and degradation is induced by Myc. Further, Cks1 expression is elevated in precancerous Emu-Myc B cells, and high levels of Cks1 are also a hallmark of Emu-Myc lymphoma and of human Burkitt lymphoma. Finally, loss of Cks1 in Emu-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.

Nyckelord

Animals

Bone Marrow Cells/cytology

Burkitt Lymphoma/*etiology

CDC2 Protein Kinase/*genetics/metabolism

Cell Proliferation

Crosses; Genetic

Cyclin-Dependent Kinase Inhibitor p27/*antagonists & inhibitors/genetics/physiology

Humans

Lymphoma; B-Cell/genetics/*physiopathology

Mice

Mice; Knockout

Mice; Transgenic

Proto-Oncogene Proteins c-myc/*genetics

Retroviridae/genetics

Tumor Cells; Cultured

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