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J. Biol. Chem., Vol. 277, Issue 7, 5145-5152, February 15, 2002
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From the Department of Microbiology and Molecular Genetics,
Michigan State University, East Lansing, Michigan 48824
The MCF-7 cell line is a model of
estrogen-dependent, antiestrogen-sensitive human breast
cancer. Antiestrogen treatment of MCF-7 cells causes dramatic decreases
in both Cdk4 and Cdk2 activities, which leads to a G1
phase cell cycle arrest. In this report, we investigate the
mechanism(s) by which Cdk4 activity is regulated in MCF-7 cells.
Through time course analysis, we demonstrate that changes in Cdk4
activity in response to estrogen or antiestrogen treatment do not
correlate directly with cyclin D1 protein levels or association. In
contrast, Cdk4 activity does correlate with changes in the level of the
Cdk inhibitor p21WAF1/Cip1. Furthermore, we show that
extracts of antiestrogen-treated cells contain a factor capable of
inhibiting the Cdk4 activity present in extracts of
estrogen-treated cells, and immunodepletion experiments identify this factor as p21WAF1/Cip1. These results
identify p21WAF1/Cip1 as an important physiological
regulator of Cdk4 complexes in human breast cancer cells.
The Cyclin-dependent Kinase Inhibitor
p21WAF1/Cip1 Is an Antiestrogen-regulated Inhibitor of Cdk4
in Human Breast Cancer Cells*
*
This work was supported by NCI Grant CA76647 from the
National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 517-353-5161;
Fax: 517-353-8957; E-mail: conrad@msu.edu.
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