The objective of the proposed research is to understand how protein- tyrosine kinase oncongenes transform cells. The major emphasis is on the fps gene of Fujinami sarcoma virus. We will characterize signal transduction pathways used by v-fps to transform cells. We have developed a pharmaco-genetic approach for identifying signal transduction intermediates used by the v-fps gene product to transduce signals to the nucleus. Elevating the protein-tyrosine kinase activity of a temperature-sensitive derivative of v-fps, leads to the rapid transcriptional activation of the recently characterized 9E3 gene whose expression correlates with transformation (Sugano et al., Cell 49, 1321,-328, 1987). Drugs that interfere with known signal transduction intermediates are used to block the induction of 9E3 gene expression. In this way, we can determine if specific signal transduction intermediates are required for v-fps to induce expression of the transformation-related 9E3 gene. The pharmacological approach involves the generation of detailed drug- sensitivity profiles (DSPs) for inhibitors of signal transduction that are diagnostic for the involvement of specific signal transduction intermediates. Using several protein kinase C requirement. In addition, we have preliminary data suggesting a requirement for protein kinase C, a cholera toxin-sensitive G-protein, phospholipase C, and phospholipase A2 in the v-fps induction of 9E3 gene expression. Experiments proposed here will directly demonstrate the involvement of these implicated signal transduction intermediates in transformation by v-fps. The data to be generated from these studies may provide new targets and strategies for cancer chemotherapy in cases where protein-tyrosine kinase activity has been implicated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA046677-03
Application #
3458702
Study Section
Virology Study Section (VR)
Project Start
1989-08-25
Project End
1994-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Hunter College
Department
Type
Schools of Arts and Sciences
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
Saqcena, Mahesh; Menon, Deepak; Patel, Deven et al. (2013) Amino acids and mTOR mediate distinct metabolic checkpoints in mammalian G1 cell cycle. PLoS One 8:e74157
Foster, David A (2013) Phosphatidic acid and lipid-sensing by mTOR. Trends Endocrinol Metab 24:272-8
Yellen, Paige; Chatterjee, Amrita; Preda, Angela et al. (2013) Inhibition of S6 kinase suppresses the apoptotic effect of eIF4E ablation by inducing TGF-?-dependent G1 cell cycle arrest. Cancer Lett 333:239-43
Yellen, Paige; Saqcena, Mahesh; Salloum, Darin et al. (2011) High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle 10:3948-56
Toschi, Alfredo; Lee, Evan; Thompson, Sebastian et al. (2010) Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells. Cancer Lett 299:72-9
Foster, David A (2010) Reduced mortality and moderate alcohol consumption: the phospholipase D-mTOR connection. Cell Cycle 9:1291-4
Lyo, Donggon; Xu, Limei; Foster, David A (2010) Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway. Biochem Biophys Res Commun 396:562-5
Toschi, Alfredo; Lee, Evan; Xu, Limei et al. (2009) Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin. Mol Cell Biol 29:1411-20
Foster, David A; Toschi, Alfredo (2009) Targeting mTOR with rapamycin: one dose does not fit all. Cell Cycle 8:1026-9
Foster, David A (2009) Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells. Biochim Biophys Acta 1791:949-55

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