# Defining protein translation dynamics in cancers with differential Myc expression

> **NIH NIH F30** · JOHNS HOPKINS UNIVERSITY · 2024 · $53,974

## Abstract

PROJECT SUMMARY
Gene amplification of the oncogene Myc is associated with increased metastasis, resistance to treatment, and
overall poor prognosis and survival across several cancers. In accordance with its role as a pro-growth
transcription factor, Myc upregulates protein synthesis globally by driving expression of ribosomal RNA,
ribosomal proteins, and protein translation initiation factors. This increase in protein synthesis capacity is
presumed to promote cancer cell growth and proliferation but also leads to dysregulated signaling in the form of
stress-response pathways usually associated with impaired proteostasis and translational stress. Key kinases
involved in these pathways include members of the integrated stress response, PERK and GCN2, but an
understanding of how Myc expression activates these stress response pathways remains underexplored. One
mechanism, however, may be through ribosome collisions, an aberrant translation event that activates GCN2,
along with the MAP3K ZAK⍺, to trigger either translation repression to prevent additional collision events or
apoptosis in severe cases. Ribosome collisions result from various translational stressors, and occur when an
elongating, trailing ribosome catches up to and collides with a stalled, leading ribosome on an mRNA transcript.
Given that stress-response pathways downstream of collisions may be hyper-active in cells with high Myc levels,
it is likely that ribosome collisions occur at a higher rate in Myc overexpression cell lines compared to cells with
lower Myc expression. As a result, these cells may be more susceptible to cellular stressors that induce ribosome
collisions as well. The central hypothesis of this proposal is therefore that upregulation of translation activity by
Myc overexpression will lead to increased apoptosis in the presence of ribosome collision-inducing drugs. I
propose to address this hypothesis through the following aims: Aim 1: Investigate the effects of Myc expression
on protein translation dynamics; Aim 2a: Assess how Myc affects ribosome collision frequency and sensitivity
to translation stress; Aim 2b: Determine if translation stress increases apoptosis in cancers with high Myc
expression. These aims will be achieved by utilizing my laboratory’s expertise in studying ribosome function and
regulation via biochemical and sequencing analysis to study translational activity and collision-induced signaling
in cell-based models for Myc overexpression and in cancer cell lines with known differential Myc expression.
Results of this work could reveal both novel therapeutic strategies for combatting the many cancer subtypes with
elevated levels of Myc and unique insights into how increased protein synthesis demands affect translation
dynamics in cancer.

## Key facts

- **NIH application ID:** 10824705
- **Project number:** 1F30CA288019-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Kate Schole
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 1
- **Project period:** 2024-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824705

## Citation

> US National Institutes of Health, RePORTER application 10824705, Defining protein translation dynamics in cancers with differential Myc expression (1F30CA288019-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10824705. Licensed CC0.

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