A role for c-myc in chemically induced renal-cell death.
A role for c-myc in chemically induced renal-cell death.
复制标题
c-myc 在化学诱导的肾细胞死亡中的作用。
DOI：
10.1128/mcb.17.11.6755
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发表时间：
1997
影响因子：
5.3
通讯作者：
Stevens,JL
中科院分区：
文献类型：
--
作者：
Zhan,Y;Cleveland,JL;Stevens,JL
包括c-myc在内的多种基因在体内和体外均可被化学毒物激活。虽然强制c-myc表达在退出生存因子后诱导细胞凋亡，但内源性c-myc基因的激活是否是毒物暴露后的凋亡信号尚不清楚。肾小管上皮是许多毒物的靶点。c-myc表达被小管损伤激活。在静止的LLC-PK1肾上皮细胞中，c-mycbut notmaxormadmRNA可被肾毒性物质-（1,2-二氯丙基）- l -半胱氨酸（DCVC）诱导。dcvc诱导的c-myc表达和凋亡动力学表明，暴露于有毒物质后，细胞死亡与c-myc表达的延长活化之间存在关联。因此，雌激素受体- myc融合构建体的长时间激活，而不是c-Myc转激活结构域被删除的构建体，足以诱导lc - pk1细胞凋亡。此外，当坏死是DCVC在亲代细胞中引起的主要细胞死亡途径时，过表达c-mycbi使细胞死亡途径偏向凋亡。DCVC还能诱导鸟氨酸脱羧酶（odc） mRNA表达，激活theodc启动子。通过DCVC激活theccpromoter需要一致的c-Myc-Max结合位点inodcintron 1。α-二氟甲基鸟氨酸抑制ODC活性可延缓dcvc诱导的细胞死亡。因此，odc是参与c-myc活化的DCVC凋亡通路中的靶基因，并参与细胞凋亡。最后，一种结构相关的细胞毒性但无基因毒性的DCVC类似物不会诱导c-myc，也不会激活thethecpromoter或诱导细胞凋亡。这些数据支持静止肾上皮细胞中凋亡细胞死亡的激活与c-myc的诱导有关的假设。这是第一个证明特定肾毒物诱导c-mycin导致基因激活和细胞死亡的研究。
A variety of genes, including c-myc, are activated by chemical toxicants in vivo and in vitro. Although enforced c-mycexpression induces apoptosis after withdrawing survival factors, it is not clear if activation of the endogenous c-mycgene is an apoptotic signal after toxicant exposure. The renal tubular epithelium is a target for many toxicants. c-mycexpression is activated by tubular damage. In quiescent LLC-PK1 renal epithelial cells, c-mycbut notmaxormadmRNA is induced by the nephrotoxicantS-(1,2-dichlorovinyl)-L-cysteine (DCVC). The kinetics of DCVC-induced c-mycexpression and apoptosis suggested an association between cell death and prolonged activation of c-mycexpression after toxicant exposure. Accordingly, prolonged activation of an estrogen receptor-Myc fusion construct, but not a construct in which a c-Myc transactivation domain had been deleted, was sufficient to induce apoptosis in LLC-PK1 cells. Moreover, under conditions in which necrosis was the predominant cell death pathway caused by DCVC in parental cells, overexpressing c-mycbiased the cell death pathway toward apoptosis. DCVC also induced ornithine decarboxylase (odc) mRNA and activated theodcpromoter. Activation of theodcpromoter by DCVC required consensus c-Myc–Max binding sites inodcintron 1. Inhibiting ODC activity with α-difluoromethylornithine delayed DCVC-induced cell death. Therefore,odcis a target gene in the DCVC apoptotic pathway involving c-mycactivation and contributes to apoptosis. Finally, a structurally related cytotoxic but nongenotoxic analog of DCVC did not induce c-mycand did not activate theodcpromoter or induce apoptosis. The data support the hypothesis that activation of apoptotic cell death in quiescent renal epithelial cells involves induction of c-myc. This is the first study to demonstrate that c-mycinduction by a specific nephrotoxicant leads to gene activation and cell death.