Butts B D, Hudson H R, Linseman D A, Le S S, Ryan K R, Bouchard R J, Heidenreich K A
Pharmacology, University of Colorado Health Science Center at Fitzsimons, Aurora, CO 80045, USA.
Mol Cell Neurosci. 2005 Oct;30(2):279-89. doi: 10.1016/j.mcn.2005.07.011.
The role of the proteasome in neuronal apoptosis is poorly understood since both anti- and pro-apoptotic effects result from proteasome inhibition. We studied the effects of proteasome inhibition in cultured rat cerebellar granule neurons. Acute exposure to proteasome inhibitors MG-132 and lactacystin blocked caspase activation induced by removal of depolarizing medium. However, chronic treatment with MG-132 activated caspases in neurons maintained in depolarizing potassium. The biphasic effect of MG-132 was hypothesized to be due to differential degradation of anti- and pro-apoptotic proteins. Accordingly, acute exposure to MG-132 inhibited the hyperphosphorylation, loss of DNA binding, ubiquitination, and degradation of the pro-survival transcription factor MEF2D induced by removal of depolarizing medium. In contrast, chronic exposure to MG-132 increased the expression and phosphorylation of c-Jun, elevated levels of the pro-apoptotic protein Bim, and triggered neuronal apoptosis, even in the presence of depolarizing medium. Thus, proteasome inhibition exerts an acute pro-survival action by stabilizing MEF2 transcription factors. However, chronic proteasome inhibition causes a build-up of phosphorylated c-Jun and Bim, which eventually overwhelms the effects of MEF2 and triggers apoptosis.
蛋白酶体在神经元凋亡中的作用尚不清楚，因为蛋白酶体抑制既会产生抗凋亡作用，也会产生促凋亡作用。我们研究了蛋白酶体抑制对培养的大鼠小脑颗粒神经元的影响。急性暴露于蛋白酶体抑制剂MG-132和乳胞素可阻断因去除去极化培养基而诱导的半胱天冬酶激活。然而，用MG-132进行慢性处理会激活维持在去极化钾环境中的神经元中的半胱天冬酶。MG-132的双相作用被认为是由于抗凋亡蛋白和促凋亡蛋白的差异降解所致。因此，急性暴露于MG-132可抑制因去除去极化培养基而诱导的促生存转录因子MEF2D的过度磷酸化、DNA结合丧失、泛素化和降解。相反，即使在存在去极化培养基的情况下，长期暴露于MG-132也会增加c-Jun的表达和磷酸化，提高促凋亡蛋白Bim的水平，并引发神经元凋亡。因此，蛋白酶体抑制通过稳定MEF2转录因子发挥急性促生存作用。然而，长期的蛋白酶体抑制会导致磷酸化的c-Jun和Bim积累，最终超过MEF2的作用并引发凋亡。
