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.
Keller
Ulrich B
UB
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN, USA.
Old
Jennifer B
JB
Dorsey
Frank C
FC
Nilsson
Jonas A
JA
Nilsson
Lisa
L
MacLean
Kirsteen H
KH
Chung
Linda
L
Yang
Chunying
C
Spruck
Charles
C
Boyd
Kelli
K
Reed
Steven I
SI
Cleveland
John L
JL
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002051:Burkitt Lymphoma / Q000209:etiology*; D016203:CDC2 Protein Kinase / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D003433:Crosses, Genetic; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured
D016271:Proto-Oncogene Proteins c-myc; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase