DDIT3 and KAT2A Proteins Regulate TNFRSF10A and TNFRSF10B Expression in Endoplasmic Reticulum Stress-mediated Apoptosis in Human Lung Cancer Cells
DDIT3 and KAT2A Proteins Regulate TNFRSF10A and TNFRSF10B Expression in Endoplasmic Reticulum Stress-mediated Apoptosis in Human Lung Cancer Cells
复制标题
DDIT3 和 KAT2A 蛋白调节人肺癌细胞内质网应激介导的细胞凋亡中 TNFRSF10A 和 TNFRSF10B 的表达。
DOI：
10.1074/jbc.m115.645333
复制
发表时间：
2015-04-24
影响因子：
4.8
通讯作者：
Liu, Xiangguo
中科院分区：
文献类型：
--
作者：
Li, Tianliang;Su, Ling;Liu, Xiangguo
TNFRSF 10A和TNFRSF 10 B是与肿瘤坏死因子相关凋亡诱导配体（TRAIL）结合并介导细胞凋亡的外源性途径的细胞表面受体。然而，TNFRSF 10A和TNFRSF 10 B的转录调控机制在很大程度上仍不清楚。在这项研究中，在TNFRSF 10A启动子区鉴定了两个推定的DDIT 3结合位点（-1636/-1625; -374/-364）和一个推定的AP-1结合位点（-304/-298）。我们发现，DDIT 3与磷酸-JUN相互作用，DDIT 3-磷酸-JUN复合物结合TNFRSF 10A启动子区域内的AP-1结合位点（-304/-298）。此外，我们证实KAT 2A与DDIT 3的N-末端区域（氨基酸1-26）物理相互作用。重要的是，KAT 2A的敲低下调了TNFRSF 10A和TNFRSF 10 B，并且显著降低了用含有TNFRSF 10A启动子的AP-1结合位点（-304/-298）的荧光素酶报告质粒转染的细胞的启动子活性，以及用含有TNFRSF 10 B启动子的DDIT 3结合位点（-276/-264）的荧光素酶报告质粒转染的细胞的启动子活性。ChIP结果表明，KAT 2 A可能参与KAT 2A中心点DDIT 3中心点磷酸-JUN复合物，或可能分别参与KAT 2A中心点DDIT 3复合物和乙酰化H3 K9/K14。此外，我们证实TNFRSF 10A介导人肺癌细胞中内质网应激引发的凋亡。总之，我们证明DDIT 3和KAT 2A协同上调TNFRSF 10A和TNFRSF 10 B。我们的研究结果强调了内质网应激诱导TNFRSF 10A和TNFRSF 10 B表达和凋亡的新机制。这些发现将有助于阐明抗癌药物介导细胞凋亡的相关机制。
TNFRSF10A and TNFRSF10B are cell surface receptors that bind to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mediate the extrinsic pathway of apoptosis. However, the mechanisms of transcriptional regulation of TNFRSF10A and TNFRSF10B remain largely uncharacterized. In this study, two putative DDIT3 binding sites (-1636/-1625; -374/-364) and a putative AP-1 binding site (-304/-298) were identified in the TNFRSF10A promoter region. We found that DDIT3 interacts with phospho-JUN, and the DDIT3-phospho-JUN complex binds to the AP-1 binding site (-304/-298) within the TNFRSF10A promoter region. In addition, we confirmed that KAT2A physically interacts with the N-terminal region (amino acids 1-26) of DDIT3. Importantly, knockdown of KAT2A down-regulated TNFRSF10A and TNFRSF10B and dramatically decreased promoter activity of cells transfected with luciferase reporter plasmid containing the AP-1 binding site (-304/-298) of the TNFRSF10A promoter, as well as cells transfected with luciferase reporter plasmid containing DDIT3 binding site (-276/- 264) of the TNFRSF10B promoter. ChIP results suggest that KAT2 A may participate in a KAT2A center dot DDIT3 center dot phospho-JUN complex, or may participate in a KAT2A center dot DDIT3 complex and acetylate H3K9/K14, respectively. Moreover, we verified that TNFRSF10A mediates apoptosis triggered by endoplasmic reticulum stress in human lung cancer cells. Collectively, we demonstrate that DDIT3 and KAT2A cooperatively up-regulate TNFRSF10A and TNFRSF10B. Our findings highlight novel mechanisms underlying endoplasmic reticulum stress-induced TNFRSF10A and TNFRSF10B expressions and apoptosis. These findings will be helpful for elucidating mechanisms related to anticancer drugs in mediating apoptosis.