Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
Mol Biol Cell. 2011 Sep;22(18):3533-40. doi: 10.1091/mbc.E11-06-0483. Epub 2011 Jul 27.
Glycogen synthase kinase 3β (GSK3β) regulates diverse physiological processes, including metabolism, development, oncogenesis, and neuroprotection. GSK3β 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 GSK3β regulates the survival of leukemia cells. We demonstrate that upon GSK3β 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 GSK3β inhibition in cell survival. GSK3β 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 GSK3β controls cell survival.
糖原合酶激酶 3β（GSK3β）调节多种生理过程，包括代谢、发育、肿瘤发生和神经保护。已报道 GSK3β 激酶活性对各种类型的癌细胞至关重要，但机制仍不清楚。在这项研究中，我们研究了 GSK3β 调节白血病细胞存活的机制。我们证明，在 GSK3β 激酶抑制后，不同类型的白血病细胞由于细胞凋亡而表现出严重的增殖缺陷。转录因子 c-Myb 被发现是 GSK3β 抑制细胞存活的主要靶标。GSK3β 的失活通过促进其泛素化介导的降解来降低 c-Myb 的表达，从而抑制 c-Myb 依赖性抗凋亡基因 Bcl2 和 survivin 的表达。共免疫沉淀、报告基因分析、染色质免疫沉淀和敲低研究表明，c-Myb 需要与转录因子 LEF-1 相互作用和合作以激活 Bcl2 和 survivin，并且这两个转录因子都是细胞存活所必需的。这些数据揭示了 GSK3β 控制细胞存活的一个未知机制。
