Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis
Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis
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DOI：
10.4161/cbt.4.11.2299
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发表时间：
2005-11-01
影响因子：
3.6
通讯作者：
El-Deiry, WS
中科院分区：
文献类型：
--
作者：
Corn, PG;Ricci, MS;El-Deiry, WS
HIF-1 是一种缺氧诱导转录因子，通过激活参与葡萄糖代谢、血管重塑和红细胞生成的基因，在细胞对缺氧的反应中发挥关键作用。我们鉴定出 Mxi1（一种 c-Myc 拮抗剂）作为缺氧诱导的新靶基因。 Mxi1 在 ARNT (HIF-1 beta) 缺陷的细胞中没有被诱导，表明 Mxi1 是 HIF-1 复合物的转录靶标。值得注意的是，c-Myc 蛋白水平在缺氧期间下降，但通过蛋白酶体抑制剂得以稳定。对缺氧期间 c-Myc 下游转录靶标的分析表明，受 c-Myc 调节的基因，例如鸟氨酸脱羧酶 (ODC)，在缺氧期间下调。相比之下，受 c-Myc 和 HIF-1 调节的基因（例如 LDH-A）则上调。 Mxi1 可防止 c-Myc 依赖性对缺氧诱导的细胞凋亡的敏感性。结果表明，缺氧期间对抗 c-Myc 信号传导的协调机制是由 c-Myc 水平降低、Mxi1 诱导和 HIF-1 转录活性的主导效应介导的。
HIF-1, a hypoxia inducible transcription factor, plays a pivotal role in the cellular response to hypoxia by activating genes involved in glucose metabolism, vascular remodeling, and erythropoiesis. We identified Mxi1, a c-Myc antagonist, as a novel target gene induced in hypoxia. Mxi1 was not induced in cells deficient in ARNT ( HIF-1 beta), suggesting that Mxi1 is a transcriptional target of the HIF-1 complex. Notably, c-Myc protein levels decreased during hypoxia but were stabilized by a proteasome inhibitor. Analysis of downstream transcriptional targets of c-Myc during hypoxia revealed that genes regulated by c-Myc, such as ornithine decarboxylase ( ODC), were downregulated during hypoxia. In contrast, genes that are regulated by c-Myc and HIF-1, such as LDH-A, were upregulated. Mxi1 protects against c-Myc-dependent sensitization to hypoxia-induced apoptosis. The results suggest a coordinated mechanism for opposing c-Myc signaling during hypoxia that is mediated by a reduction in c-Myc levels, the induction of Mxi1, and a dominant effect of HIF-1 transcriptional activity.