# Translational dysregulation of cell fate regulators drives oncogenic growth

> **NIH NIH F30** · UNIVERSITY OF WASHINGTON · 2020 · $48,410

## Abstract

Dysregulation of protein synthesis is commonly seen in cancer, yet it is unclear how this 
dysregulation affects stem cell behaviors that can promote aberrant growth. In normal development, 
protein synthesis is tightly controlled to maintain balanced cell fate decisions and proper tissue 
growth. However, during oncogenesis, translation is reprogrammed to support a wide range of 
cancer cell behaviors, such as rapid proliferation and increased survival. While previous studies 
have described oncogene-induced translational changes, there has been limited functional analysis 
of how these translational differences alter stem cell fate choice to disrupt tissue homeostasis. 
This project aims to address this gap in our fundamental understanding of oncogenic growth.
We will characterize translationally-regulated cell fate choices by manipulating 
the translational machinery in the epidermis, a tissue ideally suited for studying stem cell 
fate. We have identified translation initiation factor Eif2b5 as a positive growth 
regulator in an oncogenic HrasG12V model. Preliminary studies in embryonic murine epidermis 
reveal that Eif2b5 elevates translation rate and drives tissue growth in an oncogene- specific 
manner. Intriguingly, Eif2b5 also promotes both HrasG12V progenitor cell proliferation and 
differentiation, which have opposing effects on overall tissue growth. We now seek to understand 
how this oncogene-induced translational reprogramming disrupts normal cell fate balance to drive 
tumor formation. We will first expand our preliminary studies to mechanistically dissect how 
HrasG12V signaling induces translational upregulation. Then, we will investigate how HrasG12V 
dysregulates EIF2B5-dependent translation of cell fate regulators to promote oncogenic growth. We 
have already profiled the HrasG12V translatome and identified the subset of oncogenic genes that 
are translationally regulated by EIF2B5. From this gene set, we will characterize top candidate 
cell fate regulators to segregate the translational mechanisms governing proliferation and 
 differentiation and establish their roles in oncogenic growth.
Collectively, these studies will provide a comprehensive understanding of the 
oncogene-induced translational landscape and how it can be therapeutically targeted.

## Key facts

- **NIH application ID:** 9949660
- **Project number:** 5F30CA224951-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Yi Cai
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $48,410
- **Award type:** 5
- **Project period:** 2018-07-16 → 2021-06-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949660

## Citation

> US National Institutes of Health, RePORTER application 9949660, Translational dysregulation of cell fate regulators drives oncogenic growth (5F30CA224951-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9949660. Licensed CC0.

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