EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC.
EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC.
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DOI：
10.1158/2159-8290.cd-18-0606
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发表时间：
2019-03
期刊：
影响因子：
28.2
通讯作者：
Fagin JA
中科院分区：
文献类型：
--
作者：
Krishnamoorthy GP;Davidson NR;Leach SD;Zhao Z;Lowe SW;Lee G;Landa I;Nagarajah J;Saqcena M;Singh K;Wendel HG;Dogan S;Tamarapu PP;Blenis J;Ghossein RA;Knauf JA;Rätsch G;Fagin JA
翻译起始由帽结合和43 S前起始复合物（PIC）协调。真核起始因子1A（EIF 1A）是募集三元复合物和组装43 S PIC所必需的。甲状腺乳头状癌中的复发性EIF 1AX突变与其他驱动因素（包括RAS）相互排斥。EIF 1AX在晚期甲状腺癌中富集，在晚期甲状腺癌中它与RAS显着共存，RAS协同诱导小鼠和等基因细胞系中的肿瘤发生。C-末端EIF 1AX-A113剪接突变在晚期甲状腺癌中最常见。EIF 1AX-A113 spl变体稳定PIC并诱导ATF 4，ATF 4是细胞应激的传感器，其被选择以抑制EIF 2 α磷酸化，从而使蛋白质合成普遍增加。RAS稳定c-MYC，EIF 1AX-A113 spl增强了这种作用。ATF 4和c-MYC诱导氨基酸转运蛋白的表达并增强mTOR对氨基酸供应的敏感性。这些相互增强的事件产生对MEK、BRD 4和mTOR激酶抑制剂的治疗脆弱性。
Translation initiation is orchestrated by the cap binding and 43S pre-initiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS. EIF1AX is enriched in advanced thyroid cancers, where it displays a striking co-occurrence with RAS, which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113spl variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113spl. ATF4 and c-MYC induce expression of aminoacid transporters and enhance sensitivity of mTOR to aminoacid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4 and mTOR kinase inhibitors.