Regulation of XIAP translation and induction by MDM2 following irradiation.
Regulation of XIAP translation and induction by MDM2 following irradiation.
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DOI：
10.1016/j.ccr.2009.03.002
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发表时间：
2009-05-05
期刊：
影响因子：
50.3
通讯作者：
Zhou M
中科院分区：
文献类型：
--
作者：
Gu L;Zhu N;Zhang H;Durden DL;Feng Y;Zhou M
癌细胞中 XIAP 蛋白水平的增加与细胞应激诱导的细胞凋亡抵抗有关。在此，我们证明 XIAP 蛋白水平的上调是由 MDM2 在翻译水平上调节的。发现 MDM2 与 XIAP 5'-UTR 的 IRES 发生物理相互作用，并正向调节 XIAP IRES 活性。这种 XIAP IRES 依赖性翻译在 MDM2 转染细胞中显着增加，其中 MDM2 在细胞质中积累。辐射引发的细胞应激和 DNA 损伤诱导 MDM2 去磷酸化和细胞质定位，这也导致 IRES 依赖性 XIAP 翻译增加。 MDM2 过表达癌细胞响应辐射而上调 XIAP，导致这些细胞对辐射诱导的细胞凋亡产生抵抗。 MDM2 癌蛋白的过度表达通常存在于癌细胞中，与癌症患者对放化疗的耐药性和不良预后相关。 MDM2 被充分表征为肿瘤抑制因子 p53 的抑制剂，MDM2 的过度表达有助于癌细胞的生长优势。然而，MDM2 过度表达赋予对放射和化疗诱导的 DNA 损伤的抵抗力的机制尚未完全阐明。我们在此报告，MDM2 能够与 XIAP mRNA 结合，并在辐射引发的细胞应激期间正向调节 IRES 依赖性 XIAP 翻译。这些结果确定了 MDM2 在介导 XIAP 翻译方面具有独立于 p53 的功能，这对于影响癌细胞对放化疗的反应至关重要。
Increases in protein levels of XIAP in cancer cells have been associated with resistance to apoptosis induced by cellular stress. Herein we demonstrate that the upregulation of XIAP protein levels is regulated by MDM2 at the translational level. MDM2 was found to physically interact with the IRES of the XIAP 5′-UTR, and to positively regulate XIAP IRES activity. This XIAP IRES-dependent translation was significantly increased in MDM2-transfected cells where MDM2 accumulated in the cytoplasm. Cellular stress and DNA damage triggered by irradiation induced the dephosphorylation and cytoplasmic localization of MDM2, which also led to an increase in IRES-dependent XIAP translation. Upregulation of XIAP in MDM2-overexpressing cancer cells in response to irradiation resulted in resistance of these cells to radiation-induced apoptosis. Overexpression of the MDM2 oncoprotein, which is often found in cancer cells, is associated with resistance to chemo-radiation therapy and poor prognosis of cancer patients. MDM2 is well characterized as an inhibitor of the tumor suppressor p53, and overexpression of MDM2 contributes to a growth advantage for cancer cells. However, the mechanism by which overexpression of MDM2 confers resistance to DNA damage induced by irradiation and chemotherapy are not fully elucidated. We report here that MDM2 was able to bind to XIAP mRNA and positively regulate the IRES-dependent XIAP translation during cellular stress triggered by irradiation. These results identify a p53-independent function for MDM2 in mediating XIAP translation, which is critical in effecting cancer cell response to chemo-radiation therapy.
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