SUPPRESSION OF RAS AND MOS TRANSFORMATION BY RADICICOL

Activated versions of ras and mos oncogenes subvert the signal transdu ction pathway by mimicking transducers at the plasma membrane and cyto sol respectively. Radicicol (UCS1006), an antifungal antibiotic, had t he ability to suppress transformation by ras and mos oncogenes in a ra pid, reversible and dose-dependent manner. UCS1006 inhibited MAP kinas e activity (both ERK1 and ERK2) in untransformed as well as uas and mo s transformed cells. However, ERK2 but not ERK1 activity was constitut ively elevated in ras and mos transformed cells used in this study. In addition, a 62 kDa (kilodalton) phosphoprotein was identified whose t yrosine phosphorylation was inhibited by UCS1006, in both ras and mos transformed cells. This 62 kDa phosphoprotein, which was found to be h eavily phosphorylated on tyrosine residues only in the ras and mos tra nsformed cells but not in untransformed NIH3T3 cells, was identical to the previously described GAP-associated tyrosine phosphoprotein, p62, that is the major target for phosphorylation in cells transformed by tyrosine kinase oncogenes. These results suggest that agents such as r adicicol can suppress transformation by diverse oncogenes such as src, ras and mos at least in part by inhibiting the function of key signal transduction intermediates such as MAP kinase and GAP-associated p62.