Abstract

Tumor promoters accelerate the process of cellular transformation through alteration of normal cellular growth and differentiation processes. One approach that has yielded important information regarding the regulation of growth factor receptors and the mechanisms by which tumor promoters act is to study the interaction of tumor promoters with receptor systems. Thapsigargin is a protein kinase C-independent tumor promoter that has recently been shown to alter epidermal growth factor (EGF) receptor binding and kinase activity. Evidence suggests that the response of the receptor is due to activation by thapsigargin of a kinase that phosphorylates select sites on the EGF receptor that differ from those phosphorylated by protein kinase C. We now propose to identify these sites and to directly test their role in the action of thapsigargin through site-directed mutagenesis studies of the EGF receptor. We also plan to investigate the mechanism by which thapsigargin stimulates kinase activation. These studies provide a new approach to understanding the regulation of cellular receptors by exogenous agents, and will lead to the elucidation of new signal transduction pathways in the cell.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035541-09
Application #
3173132
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1987-09-01
Project End
1995-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Chao, T S; Abe, M; Hershenson, M B et al. (1997) Src tyrosine kinase mediates stimulation of Raf-1 and mitogen-activated protein kinase by the tumor promoter thapsigargin. Cancer Res 57:3168-73
Xiong, W; Pestell, R G; Watanabe, G et al. (1997) Cyclin D1 is required for S phase traversal in bovine tracheal myocytes. Am J Physiol 272:L1205-10
Morrison, P; Saltiel, A R; Rosner, M R (1996) Role of mitogen-activated protein kinase kinase in regulation of the epidermal growth factor receptor by protein kinase C. J Biol Chem 271:12891-6
Morrison, P; Chung, K C; Rosner, M R (1996) Mutation of Di-leucine residues in the juxtamembrane region alters EGF receptor expression. Biochemistry 35:14618-24
Kuo, W L; Abe, M; Rhee, J et al. (1996) Raf, but not MEK or ERK, is sufficient for differentiation of hippocampal neuronal cells. Mol Cell Biol 16:1458-70
Kelleher, M D; Abe, M K; Chao, T S et al. (1995) Role of MAP kinase activation in bovine tracheal smooth muscle mitogenesis. Am J Physiol 268:L894-901
Hershenson, M B; Chao, T S; Abe, M K et al. (1995) Histamine antagonizes serotonin and growth factor-induced mitogen-activated protein kinase activation in bovine tracheal smooth muscle cells. J Biol Chem 270:19908-13
Englert, C; Hou, X; Maheswaran, S et al. (1995) WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. EMBO J 14:4662-75
Chao, T S; Foster, D A; Rapp, U R et al. (1994) Differential Raf requirement for activation of mitogen-activated protein kinase by growth factors, phorbol esters, and calcium. J Biol Chem 269:7337-41
Hou, X; Johnson, A C; Rosner, M R (1994) Identification of an epidermal growth factor receptor transcriptional repressor. J Biol Chem 269:4307-12

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