Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation

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.