# Translational control of gene expression by the mTOR pathway

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $351,750

## Abstract

Project summary/abstract
Many cells can rapidly switch between growth and quiescence in response to environmental signals. How they
orchestrate the profound reprogramming of energy metabolism and biosynthetic processes that accompanies
this transformation is not well understood. This reflects an important gap in our understanding of basic growth
mechanisms that are relevant to diverse aspects of biology, ranging from normal (eg. stem cell differentiation)
to pathogenic (eg. tumorigenesis). Throughout eukaryotes, the mTOR signaling pathway is a master regulator
of the growth/quiescence switch, and is increasingly implicated common diseases such as cancer. Central
aspects of mTOR function are mediated through control of mRNA translation. Our long-term goal is to
understand how mTOR control of the translation machinery orchestrates the cellular growth status in normal
and disease contexts. The goal of this proposal is to establish the cellular functions and regulatory
mechanisms that define two classes of mRNA targets: mRNAs with 5' terminal sequences, including the
terminal oligopyrimidine (TOP) motif, that render their translation hyper-dependent on mTOR activity; and
mRNAs that utilize the non-canonical translation factor EIF4G2 to maintain mTOR-resistant translation. Our
hypothesis, based on preliminary data described herein, is that both classes are controlled by mechanisms that
detect specific mRNA-encoded features to coordinate the production of potentially thousands of proteins to
maintain the cellular growth status. To test this hypothesis, we propose in Aim 1 to use a randomized system
to quantify the translation regulatory function of all possible 5' mRNA sequences. This information will be
integrated with transcriptome-wide measurements of mTOR-regulated translation and endogenous mRNA 5'
sequences to establish the frequency and functional scope of mRNAs whose translation is controlled through a
5'-sequence-dependent mechanism. In Aim 2, we will employ a novel cell-free translation assay that we
developed to characterize the molecular mechanism that detects and regulates this class of mRNAs. Finally, in
Aim 3, we will determine the function of EIF4G2 in mTOR-independent translation, and identify its mRNA
targets and the encoded features that define them. We will accomplish these goals using a multi-disciplinary
approach that combines novel applications of high-throughput sequencing, bioinformatic analysis and classical
biochemistry. Our results will establish the molecular features that define a post-transcriptional program of
gene expression that is at the heart of cellular growth control, and add valuable insight into the underlying
mechanisms that link mTOR dysfunction to disease, including cancer, autism, and metabolic disorders.

## Key facts

- **NIH application ID:** 10000949
- **Project number:** 5R01GM125955-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Carson Cornell Thoreen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,750
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000949

## Citation

> US National Institutes of Health, RePORTER application 10000949, Translational control of gene expression by the mTOR pathway (5R01GM125955-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000949. Licensed CC0.

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