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Transforming Growth Factor ß-induced Activation of Cyclin E-cdk2 Kinase and Down-Regulation of p27^Kip1 in C3H 10T Mouse Fibroblasts^1,2,

Department of Biochemistry, Roswell Park Cancer Institute, Buffalo, New York 14263

Transforming growth factor (TGF-ß)-stimulated induction of DNA synthesis is preceded by the activation of cyclin E/cyclin-dependent kinase (cdk)2 kinase in late G₁ in C3H 10T mouse fibroblasts. TGF-ß has no effect on the steady-state level of cdk4, while having only a modest inductive effect on cyclin D1 expression. TGF-ß stimulation does, however, lead to the striking down-regulation of p27^Kip1 expression during G₁ in a manner consistent with the timing of cyclin E-cdk2 activation. Coimmunoprecipitation analysis reveals that the amount of p27^Kip1 in complexes with the cdk2 catalytic subunit is drastically reduced at the time in late G₁ when cyclin E-cdk2 activity is maximal. These data indicate that cyclin E-cdk2 is inhibited by p27^Kip1 in the growth-arrested state and that TGF-ß relieves this inhibition by down-regulating the steady-state level of the p27^Kip1 inhibitor protein, thus reducing the level of inhibitor present in complexes with cdk2.

¹ Presented at the American Association for Cancer Research (AACR) Special Conference on Transcriptional Control of Cell Growth and Differentiation, Chatham, MA, October 16–20, 1994. Submitted as an abstract for presentation at the AACR 86th annual meeting, Toronto, Canada, 1995.

² Work on this study was supported in part by a grant (to C. E. W.) from the United States Department of Agriculture (Proposal No. 9303647).

³ To whom requests for reprints should be addressed, at Department of Biochemistry, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263-0001.

Received 12/27/94. Accepted 2/17/95.

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