Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors.
Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors.
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DOI：
10.1016/j.molcel.2015.01.003
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发表时间：
2015-02-05
期刊：
影响因子：
16
通讯作者：
Chipuk, Jerry E.
中科院分区：
文献类型：
--
作者：
Serasinghe, Madhavika N.;Wieder, Shira Y.;Renault, Thibaud T.;Elkholi, Rana;Asciolla, James J.;Yao, Jonathon L.;Jabado, Omar;Hoehn, Kyle;Kageyama, Yusuke;Sesaki, Hiromi;Chipuk, Jerry E.
线粒体分裂是有丝分裂和后生动物发育所必需的，但在癌症生物学中的机制作用仍然未知。在这里，我们研究了致癌RASG 12 V介导的细胞转化对线粒体动力学机制的直接影响，并观察到动力蛋白相关蛋白1（DRP 1），线粒体网络分裂所需的蛋白质的正选择。DRP 1的缺失可防止RASG 12 V诱导的线粒体功能障碍，并使细胞对转化具有抗性。相反，在具有活化MAPK突变的人肿瘤细胞系中，这些信号的抑制导致由DRP 1缺失引发的稳健的线粒体网络重编程，导致线粒体过度融合和线粒体代谢增加。这些表型通过DRP 1丝氨酸616的ERK 1/2磷酸化机制相关联; DRP 1 S616磷酸化足以复制表型转化诱导的线粒体功能障碍，DRP 1 S616磷酸化状态将BRAFWt与BRAFV 600 E阳性病变二分。这些发现暗示线粒体分裂和DRP 1作为转化的关键调节剂，在化疗成功中具有意想不到的杠杆作用。
Mitochondrial division is essential for mitosis and metazoan development, but a mechanistic role in cancer biology remains unknown. Here, we examine the direct effects of oncogenic RASG12V mediated cellular transformation on the mitochondrial dynamics machinery and observe a positive selection for dynamin related protein 1 (DRP1), a protein required for mitochondrial network division. Loss of DRP1 prevents RASG12V-induced mitochondrial dysfunction, and renders cells resistant to transformation. Conversely, in human tumor cell lines with activating MAPK mutations, inhibition of these signals leads to robust mitochondrial network reprogramming initiated by DRP1 loss resulting in mitochondrial hyper-fusion and increased mitochondrial metabolism. These phenotypes are mechanistically linked by ERK1/2 phosphorylation of DRP1 serine 616; DRP1S616 phosphorylation is sufficient to phenocopy transformation-induced mitochondrial dysfunction, and DRP1S616 phosphorylation status dichotomizes BRAFWt from BRAFV600E positive lesions. These findings implicate mitochondrial division and DRP1 as crucial regulators of transformation with unexpected leverage in chemotherapeutic success.
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