Transforming growth factor beta-induced activation of cyclin E-cdk2 kinase and down-regulation of p27Kip1 in C3H 10T1/2 mouse fibroblasts.
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 G1 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 p27Kip1 expression during G1 in a manner consistent with the timing of cyclin E-cdk2 activation. Coimmunoprecipitation analysis reveals that the amount of p27Kip1 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 p27Kip1 in the growth-arrested state and that TGF-beta relieves this inhibition by down-regulating the steady-state level of the p27Kip1 inhibitor protein, thus reducing the level of inhibitor present in complexes with cdk2.
Ravitz
M J
MJ
Department of Biochemistry, Roswell Park Cancer Institute, Buffalo, New York 14263.
Yan
S
S
Herr
K D
KD
Wenner
C E
CE
D000818:Animals; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D005656:Fungal Proteins / Q000378:metabolism*; D016193:G1 Phase; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D016213:Cyclins; D005656:Fungal Proteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases