The Role of the Suppressor, Rsu-1, in Regulation of Ras Signal Transduction in Breast Cancer Cells
Annual rept. 2 Jun 1998-1 JUn 1999
HENRY M JACKSON FOUNDATION ROCKVILLE MD
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Epidermal growth factor EGF family of ligands bind to a number of related receptors and stimulate mitogenesis in mammary cells. Signal transduction downstream of the EGF family of receptors involves activation of the GTPase Ras and its effectors. Rsu-1, a cDNA identified as an inhibitor of Ras-induced transformation, was RA-epitope tagged and introduced into expression vectors. The HA-Rsu-1 vectors were transfected into MCF7 breast carcinoma cell lines. Transfectants were selected and tested for response to EGF and serum stimulation. RA-Rsu-1 transfectants had similar anchorage dependent growth rates as the control cell lines, but exhibited a reduction in anchorage independent growth. Analysis of Ras-dependent kinase pathways in the Rsu-1 transfectants following stimulation of starved cells with EGF or serum revealed that expression of HA-Rsu-1 resulted in an increase in activation of Erk-2 kinase and a decrease in activation of p54 Jun kinase. In addition, Rho-dependent Rho alpha kinase was inhibited but Rac and Cdc42-dependent alphaPak serine threonine kinase was not affected by Rsu-1 expression. Activation of AKT kinase by serum and EGF was unaffected by Rsu-1 expression. These results focus attention on the role of Rsu-1 inhibited pathways in Ras signaling in MCF7 breast carcinoma cell line.
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