TGFbeta-based therapeutics may potentially be successful against epithelial cancers, since this autocrine polypeptide regulator inhibits the proliferation of responsive carcinoma cells and elicits differentiation-like effects. However, the signaling pathway(s) leading to the growth inhibitory effect of TGFbeta have not been elucidated. The principal investigator's previous data provided the first direct evidence for rapid activation of cytoplasmic signaling components (Ras and the mitogen-activated protein kinse ERK1) by TGFbeta in association with growth inhibition. Additional data suggests that the effects of TGFbeta on cell cycle components may also play a role in the growth inhibitory response to TGFbeta. The principal investigator hypothesizes that TGFbeta activation of ERK1 is upstream from the effects of TGFbeta on nuclear cell cycle components in the TGFbeta signaling pathway. Accordingly, the principal investigator will examine whether the activation of ERK1 by TGFbeta kinetically precedes the effects of TGFbeta on complexes between cyclins and cyclin-dependent kinases (Cdk's) in the nucleus. It is further hypothesized that the cytoplasmic and nuclear components modulated by TGFbeta may be linked in a manner analogous to that demonstrated in yeast with regard to the growth inhibitory effects of mating pheromones. That is, the MapK cascade in yeast directly leads to phosphorylation and transcriptional activation of a Cdk inhibitor (FAR1). Thus the principal investigator plans to investigate whether TGFbeta regulation of mammalian Cdk inhibitor p27Kip1 kinetically follows TGFbeta activation of ERK1 in asynchronous cultures of epithelial cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068444-02
Application #
2376982
Study Section
Endocrinology Study Section (END)
Project Start
1996-05-01
Project End
2000-02-29
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Frey, R S; Mulder, K M (1997) TGFbeta regulation of mitogen-activated protein kinases in human breast cancer cells. Cancer Lett 117:41-50

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