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Huffington Center on Aging and Departments of Molecular and Cellular Biology and Dermatology, Baylor College of Medicine, Houston, Texas 77030 [D. C., W. X., E. B., E. E. M.]; Department of Cancer Biology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195 [C. C.]; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel [M. C-S., A. B-Z.]; Riken Tsukuba Institute, Tsukuba, Ibaraki 305-0074, Japan [S. I.]; Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106 [E. S.]; Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 [J. C.]; and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [D. E. F.]
Overexpression of the oncoprotein SKI correlates with the progression of human melanoma in vivo. SKI is known to curtail the growth inhibitory activity of tumor growth factor ß through the formation of repressive transcriptional complexes with Smad2 and Smad3 at the p21Waf-1 promoter. Here, we show that SKI also stimulates growth by activating the Wnt signaling pathway. From a yeast two-hybrid screen and immunoprecipitation studies, we identified the protein FHL2/DRAL as a novel SKI binding partner. FHL2, a LIM-only protein, binds ß-catenin and can function as either a transcriptional repressor or activator of the Wnt signaling pathway. SKI enhanced the activation of FHL2 and/or ß-catenin- regulated gene promoters in melanoma cells. Among the SKI targets were microphthalmia-associated transcription factor and Nr-CAM, two proteins associated with melanoma cell survival, growth, motility, and transformation. Transient overexpression of SKI and FHL2 in ski-/- melanocytes synergistically enhanced cell growth, and stable overexpression of SKI in a poorly clonogenic human melanoma cell line was sufficient to stimulate rapid proliferation, decreasing the number of cells in the G1 phase of the cell cycle, and dramatically increasing clonogenicity, colony size and motility. Taken together, these results suggest that by targeting members of the tumor growth factor ß and ß-catenin pathways, SKI regulates crucial events required for melanoma growth, survival, and invasion.
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