Department of Pathology, Jingmen Hubei Province First Peoples' Hospital, Jingmen, Hubei, China.
Biochem Biophys Res Commun. 2012 Apr 20;420(4):913-7. doi: 10.1016/j.bbrc.2012.03.101. Epub 2012 Mar 27.
Apoptosis repressor with caspase recruitment domain (ARC), an anti-apoptotic protein, plays an important role in the regulation of apoptosis by blocking both the extrinsic and intrinsic death pathways. However, its regulatory mechanism remains largely undefined. Here, we reported that hypoxia up-regulated the expression of ARC in p53 deficient human colon cancer cells. Moreover, ARC is a direct target of the hypoxia-inducible factor 1 (HIF-1), a key transcriptional factor for the cellular response to hypoxia. Silencing the expression of HIF-1α in SW480 colon cancer cells by RNA interference abolished hypoxia induced ARC expression. Using luciferase reporter and ChIP assay, we showed that HIF-1α directly bound to hypoxia-responsive element located at -419 to -414 of ARC gene, which is essential for HIF-1-induced expression. As a result of the increased ARC expression, TRAIL-induced apoptosis was reduced by hypoxia. These discoveries would shed novel insights on the mechanisms for ARC expression regulation and hypoxia induced inactivation of the intrinsic death pathway.
凋亡抑制因子 with caspase recruitment domain (ARC)，一种抗凋亡蛋白，通过阻断外在和内在的死亡途径，在凋亡的调节中发挥重要作用。然而，其调控机制在很大程度上仍未得到阐明。在这里，我们报道了缺氧上调了 p53 缺陷的人结肠癌细胞中 ARC 的表达。此外，ARC 是缺氧诱导因子 1 (HIF-1) 的直接靶标，HIF-1 是细胞对缺氧反应的关键转录因子。通过 RNA 干扰沉默 SW480 结肠癌细胞中 HIF-1α 的表达，可消除缺氧诱导的 ARC 表达。通过荧光素酶报告基因和 ChIP 实验，我们发现 HIF-1α 直接结合到 ARC 基因-419 到-414 位的缺氧反应元件上，这对于 HIF-1 诱导的表达是必需的。由于 ARC 表达的增加，TRAIL 诱导的细胞凋亡被缺氧所抑制。这些发现为 ARC 表达调控和缺氧诱导内在死亡途径失活的机制提供了新的见解。
