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Differential regulation of p27 and cyclin D1 by TGF‐β and EGF in C3H 10T1/2 mouse fibroblasts
Author(s) -
Ravitz Michael J.,
Yan Shaochun,
Dolce Calogero,
Kinniburgh Alan J.,
Wenner Charles E.
Publication year - 1996
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199609)168:3<510::aid-jcp3>3.0.co;2-s
Subject(s) - downregulation and upregulation , epidermal growth factor , cyclin d1 , transforming growth factor , microbiology and biotechnology , cyclin dependent kinase , cyclin , biology , cell cycle , chemistry , cell , receptor , biochemistry , gene
Previously, we found that stimulation of C3H 10T½ mouse fibroblasts with TGF‐β leads to the striking and rapid down‐regulation of p27 Kip1 expression during G1 phase. Here, we demonstrate that TGF‐β treatment of C3H 10T½ cells does not alter the steady‐state level of Kip1 message sufficiently to account for the observed down‐regulation of p27. This demonstrates that TGF‐β‐induced down regulation of p27 Kip1 occurs at a post‐transcriptional level, consistent with a degradative mechanism of p27 Kip1 down‐regulation. Epidermal growth factor (EGF) does not lead to the rapid down‐regulation of p27 observed following treatment of cells with TGF‐β. Also in contrast with TGF‐β, EGF causes a strong upregulation of cyclin D1, while neither growth factor affects cdk4 protein levels. These results imply that in this cell type TGF‐β overcomes an inhibitory threshold to cdk activation by cyclin‐dependent kinase inhibitors primarily through down‐regulation of p27, while EGF overcomes this threshold predominantly through upregulation of cyclin D1 levels. This divergence in pathways may explain why TGF‐β‐induced cell cycle kinetics are slower than those of EGF in these cells, and the ability of TGF‐β to delay EGF‐induced cell cycle kinetics to its own, slower kinetics. In support of this hypothesis, TGF‐β prevents EGF‐induced upregulation of cyclin D1 levels, while TGF‐β is still able to induce p27 down‐regulation even in the presence of EGF. In contrast to the case with p27 degradation, neither TGF‐β nor EGF have an observable effect on the steady‐state levels of p21 in this cell type. © 1996 Wiley‐Liss, Inc.