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Dual DNA Rulers to Study the Mechanism of Ribosome Translocation with Single-Nucleotide Resolution
Published on: July 8, 2019
Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation
1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Abstract:
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.
Insights
Oncogenic Ras hinders thioredoxin-interacting protein (TXNIP) production by slowing ribosome movement on its mRNA. This Ras-driven translational repression occurs despite overall increased protein synthesis in cancer cells.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Metabolism
Background:
- Oncogenic Ras promotes aerobic glycolysis for cellular growth.
- Thioredoxin-interacting protein (TXNIP) inhibits glucose uptake and is often downregulated in cancers.
- Ras activation was previously shown to suppress TXNIP transcription and translation.
Purpose of the Study:
- To investigate how Ras affects TXNIP translation independently of transcriptional effects.
- To elucidate the mechanism by which Ras represses TXNIP protein synthesis.
Main Methods:
- Developed a system to study Ras-mediated TXNIP translation without transcriptional interference.
- Utilized mRNA variants with randomized or optimized codons to assess sequence-independent effects.
- Investigated the role of the nascent polypeptide chain in translational repression.
Main Results:
- Ras globally increases protein translation but specifically suppresses TXNIP protein synthesis.
- Ras reduces ribosome transit rate through the TXNIP mRNA coding region.
- Translational repression of TXNIP by Ras is independent of mRNA secondary structure, miRNAs, RNA-binding proteins, and codon usage.
- The N-terminal region of the growing TXNIP polypeptide is identified as the target for Ras-dependent repression.
Conclusions:
- Ras suppresses TXNIP translation elongation through a mechanism targeting the nascent polypeptide.
- This study reveals a novel aspect of Ras-dependent metabolic reprogramming in cancer.
- Understanding this mechanism provides insight into cancer cell metabolism and potential therapeutic targets.
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