线粒体分裂
生物
磷酸化
细胞生物学
MAPK/ERK通路
基因敲除
GTP酶
线粒体
DNAJA3公司
癌症研究
细胞凋亡
线粒体DNA
线粒体融合
遗传学
基因
作者
Jennifer A. Kashatus,Aldo Nascimento,Lindsey J. Myers,Annie Sher,Frances L. Byrne,Kyle L. Hoehn,Christopher M. Counter,David F. Kashatus
出处
期刊:Molecular Cell
[Elsevier]
日期:2015-02-01
卷期号:57 (3): 537-551
被引量:554
标识
DOI:10.1016/j.molcel.2015.01.002
摘要
Summary
Ras is mutated in up to 30% of cancers, including 90% of pancreatic ductal adenocarcinomas, causing it to be constitutively GTP-bound, and leading to activation of downstream effectors that promote a tumorigenic phenotype. As targeting Ras directly is difficult, there is a significant effort to understand the downstream biological processes that underlie its protumorigenic activity. Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer. Finally, this phosphorylation is required for Ras-associated mitochondrial fission, and its inhibition is sufficient to block xenograft growth. Collectively, these data suggest mitochondrial fission may be a target for treating MAPK-driven malignancies.
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