GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb.
GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb.
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DOI：
10.1091/mbc.e11-06-0483
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发表时间：
2011-09
影响因子：
3.3
通讯作者：
Ten Dijke P
中科院分区：
文献类型：
--
作者：
Zhou F;Zhang L;van Laar T;van Dam H;Ten Dijke P
c-Myb水平是白血病细胞对GSK 3 β激酶抑制反应的决定因素，这对于治疗白血病和具有c-Myb扩增的癌症特别有意义。糖原合成酶激酶3β（GSK 3 β）调节多种生理过程，包括代谢、发育、肿瘤发生和神经保护。据报道，GSK 3 β激酶活性对各种类型的癌细胞至关重要，但其机制仍然难以捉摸。在这项研究中，我们研究了GSK 3 β调节白血病细胞存活的机制。我们证明，在GSK 3 β激酶抑制后，不同类型的白血病细胞由于凋亡而表现出严重的增殖缺陷。发现转录因子c-Myb是细胞存活中GSK 3 β抑制的主要靶点。GSK 3 β失活通过促进c-Myb的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Bcl 2和Survivin的表达。免疫共沉淀，报告分析，染色质免疫沉淀和敲除研究表明，c-Myb需要相互作用和合作的转录因子LEF-1的Bcl 2和生存素的激活，这两个转录因子是细胞生存所必需的。这些数据揭示了GSK 3 β控制细胞存活的未知机制。
The level of c-Myb is a determining factor in the response of leukemia cells to GSK3β kinase inhibiton, which is of particular interest for the therapy of leukemia and cancers that have c-Myb amplifications. 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.