Glycogen synthase kinase 3 beta (GSK3 beta) regulates diverse physiological processes, including metabolism, development, oncogenesis, and neuroprotection. GSK3 beta kinase activity has been... Show moreGlycogen synthase kinase 3 beta (GSK3 beta) regulates diverse physiological processes, including metabolism, development, oncogenesis, and neuroprotection. GSK3 beta kinase activity has been reported to be critical for various types of cancer cells, but the mechanism has remained elusive. In this study we examine the mechanism by which GSK3 beta regulates the survival of leukemia cells. We demonstrate that upon GSK3 beta kinase inhibition different types of leukemia cells show severe proliferation defects as a result of apoptosis. The transcription factor c-Myb is found to be the main target of GSK3 beta inhibition in cell survival. GSK3 beta inactivation reduces the expression of c-Myb by promoting its ubiquitination-mediated degradation, thereby inhibiting the expression of c-Myb-dependent antiapoptotic genes Bcl2 and survivin. Coimmunoprecipitation, reporter assays, chromatin immunoprecipitation, and knockdown studies show that c-Myb needs to interact and cooperate with transcription factor LEF-1 in the activation of Bcl2 and survivin and that both transcription factors are required for cell survival. These data reveal an as-yet-unknown mechanism by which GSK3 beta controls cell survival. Show less
