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

Ulrich B Keller; Jennifer B Old; Frank C Dorsey; Jonas A Nilsson; Lisa Nilsson; Kirsteen H MacLean; Linda Chung; Chunying Yang; Charles Spruck; Kelli Boyd; Steven I Reed; John L Cleveland

doi:10.1038/sj.emboj.7601691

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

Ulrich B Keller, Jennifer B Old, Frank C Dorsey, Jonas A Nilsson, Lisa Nilsson, Kirsteen H MacLean, Linda Chung, Chunying Yang, Charles Spruck, Kelli Boyd, Steven I Reed, John L Cleveland

UWA Centre for Medical Research (affiliated with the Harry Perkins Institute of Medical Research)

Research output: Contribution to journal › Article › peer-review

84 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	2562-74
Number of pages	13
Journal	The EMBO Journal
Volume	26
Issue number	10
DOIs	https://doi.org/10.1038/sj.emboj.7601691
Publication status	Published - 16 May 2007

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

abstract = "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.",

keywords = "Animals, Bone Marrow Cells/cytology, Burkitt Lymphoma/etiology, CDC2 Protein Kinase/genetics, Cell Proliferation, Crosses, Genetic, Cyclin-Dependent Kinase Inhibitor p27/antagonists & inhibitors, Humans, Lymphoma, B-Cell/genetics, Mice, Mice, Knockout, Mice, Transgenic, Proto-Oncogene Proteins c-myc/genetics, Retroviridae/genetics, Tumor Cells, Cultured",

author = "Keller, {Ulrich B} and Old, {Jennifer B} and Dorsey, {Frank C} and Nilsson, {Jonas A} and Lisa Nilsson and MacLean, {Kirsteen H} and Linda Chung and Chunying Yang and Charles Spruck and Kelli Boyd and Reed, {Steven I} and Cleveland, {John L}",

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doi = "10.1038/sj.emboj.7601691",

language = "English",

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T1 - Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis

AU - Keller, Ulrich B

AU - Old, Jennifer B

AU - Dorsey, Frank C

AU - Nilsson, Jonas A

AU - Nilsson, Lisa

AU - MacLean, Kirsteen H

AU - Chung, Linda

AU - Yang, Chunying

AU - Spruck, Charles

AU - Boyd, Kelli

AU - Reed, Steven I

AU - Cleveland, John L

PY - 2007/5/16

Y1 - 2007/5/16

N2 - 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.

AB - 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.

KW - Animals

KW - Bone Marrow Cells/cytology

KW - Burkitt Lymphoma/etiology

KW - CDC2 Protein Kinase/genetics

KW - Cell Proliferation

KW - Crosses, Genetic

KW - Cyclin-Dependent Kinase Inhibitor p27/antagonists & inhibitors

KW - Humans

KW - Lymphoma, B-Cell/genetics

KW - Mice

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Proto-Oncogene Proteins c-myc/genetics

KW - Retroviridae/genetics

KW - Tumor Cells, Cultured

U2 - 10.1038/sj.emboj.7601691

DO - 10.1038/sj.emboj.7601691

M3 - Article

C2 - 17464290

SN - 0261-4189

VL - 26

SP - 2562

EP - 2574

JO - The EMBO Journal

JF - The EMBO Journal

IS - 10

ER -

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

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