A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells.
A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells.
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DOI：
10.1016/j.celrep.2017.06.061
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发表时间：
2017-07-11
期刊：
影响因子：
8.8
通讯作者：
Elledge SJ
中科院分区：
文献类型：
--
作者：
Martin TD;Cook DR;Choi MY;Li MZ;Haigis KM;Elledge SJ
KRAS癌基因的激活突变在肿瘤中非常普遍，特别是结肠、肺和胰腺的肿瘤。为了更好地了解K-Ras突变细胞生长所依赖的遗传依赖性，我们在两对等基因细胞系中采用了全基因组CRISPR功能丧失筛选。由于必需基因的丢失在基于CRISPR的筛选中是一致有毒的，我们还开发了一个靶向必需基因的shRNA文库。这些方法发现了大量的蛋白质，其损失导致K-Ras突变细胞生长的选择性降低。通路分析显示，这些基因中的许多在线粒体中起作用。为了验证，我们使用基于CRISPR的基因组工程生成了等基因细胞系对，这证实了K-Ras突变细胞对这些线粒体途径的依赖性。最后，我们发现线粒体抑制剂减少了体内K-Ras突变肿瘤的生长，推进了靶向K-Ras驱动的恶性肿瘤的策略。
Activating mutations in the KRAS oncogene are highly prevalent in tumors, especially those of the colon, lung, and pancreas. To better understand the genetic dependencies that K-Ras mutant cells rely upon for their growth, we employed whole-genome CRISPR loss of function screens in two isogenic pairs of cell lines. Since loss of essential genes is uniformly toxic in CRISPR-based screens we also developed an shRNA library targeting essential genes. These approaches uncovered a large set of proteins whose loss results in the selective reduction of K-Ras mutant cell growth. Pathway analysis revealed that many of these genes function in the mitochondria. For validation, we generated isogenic pairs of cell lines using CRISPR-based genome engineering, which confirmed the dependency of K-Ras mutant cells on these mitochondrial pathways. Finally, we found that mitochondrial inhibitors reduce the growth of K-Ras mutant tumors in vivo, advancing strategies to target K-Ras-driven malignancy.
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抑制线粒体翻译是人类急性髓样白血病的治疗策略。
影响因子：
50.3
作者：
Skrtić M;Sriskanthadevan S;Jhas B;Gebbia M;Wang X;Wang Z;Hurren R;Jitkova Y;Gronda M;Maclean N;Lai CK;Eberhard Y;Bartoszko J;Spagnuolo P;Rutledge AC;Datti A;Ketela T;Moffat J;Robinson BH;Cameron JH;Wrana J;Eaves CJ;Minden MD;Wang JC;Dick JE;Humphries K;Nislow C;Giaever G;Schimmer AD
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影响因子：
50.3
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通讯作者：
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影响因子：
8
作者：
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通讯作者：
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