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.

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

Old, Jennifer B (författare)
Dorsey, Frank C (författare)
Nilsson, Jonas AUmeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet),Nilsson (författare)
Nilsson, LisaUmeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet),Heby(Swepub:umu)lini0002 (författare)
MacLean, Kirsteen H (författare)
Chung, Linda (författare)
Yang, Chunying (författare)
Spruck, Charles (författare)
Boyd, Kelli (författare)
Reed, Steven I (författare)
Cleveland, John L (författare)
Umeå universitetInstitutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet) (creator_code:org_t)

Av författaren/redakt...: Keller, Ulrich B; Old, Jennifer B; Dorsey, Frank C; Nilsson, Jonas A; Nilsson, Lisa; MacLean, Kirstee ...; visa fler...; Chung, Linda; Yang, Chunying; Spruck, Charles; Boyd, Kelli; Reed, Steven I; Cleveland, John ...; visa färre...

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