Transforming growth factor beta-induced activation of cyclin E-cdk2 kinase and down-regulation of p27Kip1 in C3H 10T1/2 mouse fibroblasts
Ravitz, M.J.; Yan, S.; Herr, K.D.; Wenner, C.E.
Cancer Research 55(7): 1413-1416
1995
ISSN/ISBN: 0008-5472 PMID: 7882344 Document Number: 447386
Transforming growth factor (TGF-beta)-stimulated induction of DNA synthesis is preceded by the activation of cyclin E/cyclin-dependent kinase (cdk)2 kinase in late G-1 in C3H 10T1/2 mouse fibroblasts. TGF-beta has no effect on the steady-state level of cdk4, while having only a modest inductive effect on cyclin D1 expression. TGF-beta stimulation does, however, lead to the striking down-regulation of p27-Kip1 expression during G-1 in a manner consistent with the timing of cyclin E-cdk2 activation. Co-immunoprecipitation analysis reveals that the amount of p27-Kip1 in complexes with the cdk2 catalytic subunit is drastically reduced at the time in late G-1 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-beta 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.