MAD1 and p27KIP1 cooperate to promote terminal differentiation of granulocytes and to inhibit Myc expression and cyclin E-CDK2 activity

被引:55
作者
McArthur, GA
Foley, KP
Fero, ML
Walkley, CR
Deans, AJ
Roberts, JM
Eisenman, RN
机构
[1] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA
[2] Peter MacCallum Canc Inst, Div Res, Melbourne, Vic 3002, Australia
[3] Peter MacCallum Canc Inst, Div Haematol Med Oncol, Melbourne, Vic 3002, Australia
关键词
D O I
10.1128/MCB.22.9.3014-3023.2002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
To understand how cellular differentiation is coupled to withdrawal from the cell cycle, we have focused on two negative regulators of the cell cycle, the MYC antagonist MAD1 and the cyclin-dependent kinase inhibitor p27(KIP1). Generation of Mad1/p27(KIP1) double-null mice revealed a number of synthetic effects between the null alleles of Mad1 and p27(KIP1), including embryonic lethality, increased proliferation, and impaired differentiation of granulocyte precursors. Furthermore, with granulocyte cell lines derived from the Mad1/p27(KIP1) double-null mice, we observed constitutive Myc expression and cyclin E-CDK2 kinase activity as well as impaired differentiation following treatment with an inducer of differentiation. By contrast, similar treatment of granulocytes from Mad1 or p27(KIP1) single-null mice resulted in differentiation accompanied by downregulation of both Myc expression and cyclin E-CDK2 kinase activity. In the double-null granulocytic cells, addition of a CDK2 inhibitor in the presence of differentiation inducer was sufficient to restore differentiation and reduce Myc levels. We conclude that Mad1 and p27(KIP1) operate, at least in part, by distinct mechanisms to downregulate CDK2 activity and Myc expression in order to promote cell cycle exit during differentiation.
引用
收藏
页码:3014 / 3023
页数:10
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