Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal.
Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal.
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发表时间：
2000
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通讯作者：
M. Hetman;J. E. Cavanaugh;D. Kimelman;Z. Xia
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作者：
M. Hetman;J. E. Cavanaugh;D. Kimelman;Z. Xia
糖原合成酶激酶-3 β（GSK3 β）活性受保护神经元免于凋亡的若干信号转导级联负调节，包括磷脂酰肌醇-3激酶（PI-3激酶）途径。这提示了一种有趣的可能性，即GSK 3 β的激活可能有助于神经元凋亡。因此，我们评估了GSK3 β在培养的皮层神经元中由营养因子戒断或PI-3激酶抑制诱导的凋亡中的作用。神经元进行了几种凋亡范例，包括血清剥夺，血清剥夺结合暴露于NMDA受体拮抗剂，或PI-3激酶抑制剂的治疗。这些处理均导致皮层神经元中GSK3 β活性的刺激，其先于细胞凋亡的诱导。抑制性GSK3 β结合蛋白或GSK3 β显性干扰形式的表达减少神经元凋亡，表明GSK3 β有助于营养因子戒断诱导的凋亡。此外，神经元中GSK3 β的过表达增加了细胞凋亡，表明这种酶的激活足以触发程序性细胞死亡。尽管β-连环蛋白的不稳定是GSK 3 β激活的重要生理效应，但未被GSK 3 β不稳定的突变β-连环蛋白的表达并不能防止细胞凋亡。我们的结论是GSK3 β的抑制是PI-3激酶激活保护神经元免于程序性细胞死亡的机制之一。
Glycogen synthase kinase-3beta (GSK3beta) activity is negatively regulated by several signal transduction cascades that protect neurons against apoptosis, including the phosphatidylinositol-3 kinase (PI-3 kinase) pathway. This suggests the interesting possibility that activation of GSK3beta may contribute to neuronal apoptosis. Consequently, we evaluated the role of GSK3beta in apoptosis in cultured cortical neurons induced by trophic factor withdrawal or by PI-3 kinase inhibition. Neurons were subjected to several apoptotic paradigms, including serum deprivation, serum deprivation combined with exposure to NMDA receptor antagonists, or treatment with PI-3 kinase inhibitors. These treatments all led to stimulation of GSK3beta activity in cortical neurons, which preceded the induction of apoptosis. Expression of an inhibitory GSK3beta binding protein or a dominant interfering form of GSK3beta reduced neuronal apoptosis, suggesting that GSK3beta contributes to trophic factor withdrawal-induced apoptosis. Furthermore, overexpression of GSK3beta in neurons increased apoptosis, indicating that activation of this enzyme is sufficient to trigger programmed cell death. Although destabilization of beta-catenin is an important physiological effect of GSK3beta activation, expression of a mutant beta-catenin that is not destabilized by GSK3beta did not protect against apoptosis. We conclude that inhibition of GSK3beta is one of the mechanisms by which PI-3 kinase activation protects neurons from programmed cell death.