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Radicicol Suppresses Transformation and Restores Tropomyosin-2 Expression in Both ras- and MEK- transformed Cells without Inhibiting the Raf/MEK/ERK Signaling Cascade¹

Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Biologics Evaluation & Research, Bethesda, Maryland 20892-4555 [P. N. K., R. A. J. J.], Department of Medicine, Beth Israel Deaconess Medical Center [E. J., B. C. M., J. W. M.], and Harvard Medical School, Boston, Massachusetts 02215 [E. J., J. W. M.]

The antibiotic radicicol suppresses transformation in a variety of transformed cells. The antineoplastic effects of the drug have been attributed to the degradation of Raf and the inactivation of the Ras/Raf/ mitogen-activated protein kinase kinase (MEK)/ extracellular signal-regulated kinase (ERK) signaling cascade. Here we demonstrate that radicicol induces cell spreading, suppresses anchorage-independent cell growth, and increases the expression of the high-molecular weight tropomyosin isoform TM-2 in cells stably expressing a constitutively active form of MEK-1 as well as in ras-transformed cells. Furthermore, the reverting effects of the drug are achieved at concentrations below those required to deplete Raf from the cell or to inhibit the phosphorylation of ERK or its substrates Elk and pp90^RSK. In contrast, low concentrations of radicicol significantly inhibited activator protein (AP-1) and serum response factor (SRF)-mediated transcription. The lack of correlation between the effects of radicicol on cell phenotype and on the signaling activities of the Raf/MEK/ERK pathway indicate that Raf depletion or disruption of proximal signaling events in the mitogen-activated protein kinase pathway are not the predominant mechanisms by which the drug suppresses the transformed phenotype. Our observation that low concentrations of radicicol block transcriptional activities mediated by AP-1 and SRF suggests that interference with signaling upstream of these transcription factors may contribute to the reverting effects of the drug.

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				R. A. J. Janssen, P. N. Kim, J. W. Mier, and D. K. Morrison Overexpression of Kinase Suppressor of Ras Upregulates the High-Molecular-Weight Tropomyosin Isoforms in ras-Transformed NIH 3T3 Fibroblasts Mol. Cell. Biol., March 1, 2003; 23(5): 1786 - 1797. [Abstract] [Full Text] [PDF]