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 #
5R01CA068444-04
Application #
2882429
Study Section
Endocrinology Study Section (END)
Program Officer
Freeman, Colette S
Project Start
1996-05-01
Project End
2001-02-28
Budget Start
1999-03-01
Budget End
2001-02-28
Support Year
4
Fiscal Year
1999
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
Tang, Qian; Staub, Cory M; Gao, Guofeng et al. (2002) A novel transforming growth factor-beta receptor-interacting protein that is also a light chain of the motor protein dynein. Mol Biol Cell 13:4484-96
Yue, J; Mulder, K M (2001) Transforming growth factor-beta signal transduction in epithelial cells. Pharmacol Ther 91:1-34
Yue, J; Mulder, K M (2000) Requirement of Ras/MAPK pathway activation by transforming growth factor beta for transforming growth factor beta 1 production in a Smad-dependent pathway. J Biol Chem 275:30765-73
Yue, J; Mulder, K M (2000) Activation of the mitogen-activated protein kinase pathway by transforming growth factor-beta. Methods Mol Biol 142:125-31
Mulder, K M (2000) Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev 11:23-35
Yue, J; Hartsough, M T; Frey, R S et al. (1999) Cloning and expression of a rat Smad1: regulation by TGFbeta and modulation by the Ras/MEK pathway. J Cell Physiol 178:387-96
Yue, J; Frey, R S; Mulder, K M (1999) Cross-talk between the Smad1 and Ras/MEK signaling pathways for TGFbeta. Oncogene 18:2033-7
Liu, X; Yue, J; Frey, R S et al. (1998) Transforming growth factor beta signaling through Smad1 in human breast cancer cells. Cancer Res 58:4752-7
Hartsough, M T; Mulder, K M (1997) Transforming growth factor-beta signaling in epithelial cells. Pharmacol Ther 75:21-41
Frey, R S; Mulder, K M (1997) TGFbeta regulation of mitogen-activated protein kinases in human breast cancer cells. Cancer Lett 117:41-50

Showing the most recent 10 out of 12 publications