Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis
Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis
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DOI：
10.1038/sj.cdd.4402216
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发表时间：
2007-12-01
影响因子：
12.4
通讯作者：
Gaiddon, C.
中科院分区：
文献类型：
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作者：
Benosman, S.;Gross, I.;Gaiddon, C.
MDMX已被证明在DNA损伤后的分裂细胞中调节P53。在这项研究中，我们研究了MDMX在经历细胞死亡的神经元原代培养中的作用。我们发现，DNA损伤，但膜启动的凋亡应激(谷氨酸受体；淀粉样蛋白P前体)或生存因子剥夺下调MDMX蛋白水平。ShRNA诱导的细胞凋亡提示MDMX是神经元存活所必需的。蛋白水解酶抑制剂可阻止神经毒药治疗后MDMX的丢失，提示蛋白稳定性受到调节。一些，但不是全部，神经毒性应激诱导丝氨酸367处MDMX的磷酸化，进一步支持蛋白质水平的调节。有趣的是，我们发现依赖于刺激，P53或E2F1被诱导，但MDMX的过表达抑制了这两种促凋亡因子的转录活性，并在神经毒性应激下维持神经元的存活。综上所述，我们的数据表明，MDMX是神经元中的一种抗凋亡因子，其降解可由各种应激诱导，并允许在神经元凋亡过程中激活P53和E2F-1。
MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death. We found that DNA damage, but also membrane-initiated apoptotic stresses (glutamate receptor; Amyloid P precursor) or survival factor deprivation downregulated MDMX protein levels. Forced downregulation of murine double minute X (MDMX) by shRNA induced apoptosis suggesting that MDMX is required for survival in neurons., Protease inhibitors prevented the loss of MDMX after neurotoxic treatments, indicating a regulation of protein stability. Some, but not all, neurotoxic stresses induced phosphorylation of MDMX at serine 367, further supporting regulation at the protein level. Interestingly, we found that depending on the stimulus either p53 or E2F1 was induced, but overexpression of MDMX inhibited the transcriptional activity of both proapoptotic factors, and maintained neuronal viability upon neurotoxic stresses. Taken together, our data show that MDMX is an antiapoptotic factor in neurons, whose degradation is induced by various stresses and allows activation of p53 and E2F-1 during neuronal apoptosis.