Our long-term objective is to understand cell transformation by DNA tumor viruses. The transforming proteins of these viruses exert their effects, at least in part, by associating with cellular proteins involved in growth regulation. We will study nature and functional consequences of the association of the polyoma middle T antigen (mT) with protein phosphatase 2A (PP2A), pp60c-src and phosphatidylinositol-3 (PI-3) kinase, using a combination of genetic analysis of mT and biochemical analysis of cellular growth control signalling pathways. We will study mechanisms by which mT transactivates cellular growth control genes, including c-fos and c-jun, and will explore the involvement of ras and raf in mT-mediated transactivation and cell transformation. Neuroblastoma cells express a neuronal form of pp60c-src, with an altered Src homology 3 (SH3) domain. We will seek to identify proteins that bind differentially to the SH3 domains of the neuronal and fibroblastic forms of pp60c-src, to increase our understanding of mechanisms by which pp60c-src affects cell growth and differentiation. Finally we will study mechanisms of transactivation by p53, the association of p53 with the cellular protein, MDM2, and cell cycle control by p53, with emphasis on the possible role of phosphorylation in these processes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA013884-30
Application #
6628056
Study Section
Virology Study Section (VR)
Program Officer
Wong, May
Project Start
1975-09-01
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2005-01-31
Support Year
30
Fiscal Year
2003
Total Cost
$420,034
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yanochko, Gina M; Eckhart, Walter (2006) Type I insulin-like growth factor receptor over-expression induces proliferation and anti-apoptotic signaling in a three-dimensional culture model of breast epithelial cells. Breast Cancer Res 8:R18
Arbet-Engels, C; Tartare-Deckert, S; Eckhart, W (1999) C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor. J Biol Chem 274:5422-8
Arbet-Engels, C; Janknecht, R; Eckhart, W (1999) Role of focal adhesion kinase in MAP kinase activation by insulin-like growth factor-I or insulin. FEBS Lett 454:252-6
Kanemitsu, M Y; Jiang, W; Eckhart, W (1998) Cdc2-mediated phosphorylation of the gap junction protein, connexin43, during mitosis. Cell Growth Differ 9:13-21
Kanemitsu, M Y; Loo, L W; Simon, S et al. (1997) Tyrosine phosphorylation of connexin 43 by v-Src is mediated by SH2 and SH3 domain interactions. J Biol Chem 272:22824-31
Warn-Cramer, B J; Lampe, P D; Kurata, W E et al. (1996) Characterization of the mitogen-activated protein kinase phosphorylation sites on the connexin-43 gap junction protein. J Biol Chem 271:3779-86
Lau, A F; Kurata, W E; Kanemitsu, M Y et al. (1996) Regulation of connexin43 function by activated tyrosine protein kinases. J Bioenerg Biomembr 28:359-68
Glenn, G M; Eckhart, W (1995) Amino-terminal regions of polyomavirus middle T antigen are required for interactions with protein phosphatase 2A. J Virol 69:3729-36
Rigaudy, P; Simon, S; Hunter, T et al. (1994) Antibodies specific for the neuronal form of the Src protein elicited by an antigenized antibody. DNA Cell Biol 13:585-91
Srinivas, S; Schonthal, A; Eckhart, W (1994) Polyomavirus middle-sized tumor antigen modulates c-Jun phosphorylation and transcriptional activity. Proc Natl Acad Sci U S A 91:10064-8

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