Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells.

Miao Chen,Haohui Sun,Han Yang,Marc R Gartenberg,Wuguo Deng,Dingbo Shi,Melinda S Borrie,Changlin Zhang,Qian Long,Ben Montpetit

doi:10.1371/journal.pgen.1009899

Abstract

The robust proliferation of cancer cells requires vastly elevated levels of protein synthesis, which relies on a steady supply of aminoacylated tRNAs. Delivery of tRNAs to the cytoplasm is a highly regulated process, but the machinery for tRNA nuclear export is not fully elucidated. In this study, using a live cell imaging strategy that visualizes nascent transcripts from a specific tRNA gene in yeast, we identified the nuclear basket proteins Mlp1 and Mlp2, two homologs of the human TPR protein, as regulators of tRNA export. TPR expression is significantly increased in lung cancer tissues and correlated with poor prognosis. Consistently, knockdown of TPR inhibits tRNA nuclear export, protein synthesis and cell growth in lung cancer cell lines. We further show that NXF1, a well-known mRNA nuclear export factor, associates with tRNAs and mediates their transport through nuclear pores. Collectively, our findings uncover a conserved mechanism that regulates nuclear export of tRNAs, which is a limiting step in protein synthesis in eukaryotes.

Highlights

Protein synthesis levels are tightly controlled to match the demands of cell growth
Amino acids are the building blocks for proteins, and each is carried to ribosomes for protein synthesis by its own specific transport RNAs
Our previous study discovered that transport RNAs (tRNAs) genes in yeast associate with Nuclear pore complexes (NPCs) to coordinate tRNA synthesis with nuclear export

Summary

Introduction

Protein synthesis levels are tightly controlled to match the demands of cell growth. The demand for increased protein synthesis is greatest during the uncontrolled proliferation of cancer cells. Differences in transcription of a subset of tRNA genes appear to drive the differences in tRNA content between cancerous and differentiated cells [3]. A causal link between tRNA levels and cancer was suggested with the demonstration that artificial overexpression of the initiator methionine tRNA (tRNAiMet) promoted cell growth [4]. A more recent study found that tRNAGlu(UUC) and tRNAArg(CCG) were upregulated in breast cancer cells, and enhanced the stability as well as translation of mRNA transcripts enriched for their codons, shifting the cellular proteomics to a pro-metastatic state [5]

Methods

Results

Discussion

Conclusion