Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation

作     者：Ye, Zhizhou Ayer, Donald E. 

作者机构：Univ Utah Huntsman Canc Inst Dept Oncol Sci Salt Lake City UT 84112 USA 

出 版 物：《MOLECULAR AND CELLULAR BIOLOGY》 (分子生物学与细胞生物学)

年 卷 期：2018年第38卷第20期

页      面：e00178-18-e00178-18页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：NIH [R01 GM055668-14A1] Department of Defense [BC133708] National Cancer Institute of the National Institutes of Health [P30CA042014] Huntsman Cancer Foundation 

主　　题：oncogenic Ras TXNIP translation elongation protein synthesis metabolic reprogramming Warburg effect glucose MondoA metabolic regulation translational control 

摘      要：Oncogenic Ras upregulates aerobic glycolysis to meet the bioenergetic and biosynthetic demands of rapidly growing cells. In contrast, thioredoxin-interacting protein (TXNIP) is a potent inhibitor of glucose uptake and is frequently downregulated in human cancers. Our laboratory previously discovered that Ras activation suppresses TXNIP transcription and translation. In this study, we developed a system to study how Ras affects TXNIP translation in the absence of transcriptional effects. We show that whereas Ras drives a global increase in protein translation, it suppresses TXNIP protein synthesis by reducing the rate at which ribosomes transit the coding region of TXNIP mRNA. To investigate the underlying mechanism(s), we randomized or optimized the codons in the TXNIP message without altering the TXNIP primary amino acid sequence. Translation from these mRNA variants was still repressed by Ras, implying that mRNA secondary structure, microRNAs (miRNAs), RNA binding proteins, or codon usage does not contribute to the blockade of TXNIP synthesis. Rather, we show that the N terminus of the growing TXNIP polypeptide is the target for Ras-dependent translational repression. Our work demonstrates how Ras suppresses TXNIP translation elongation in the face of a global upregulation of protein synthesis and provides new insight into Ras-dependent metabolic reprogramming.