# Regulators of Tumorigenesis

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $380,114

## Abstract

REGULATORS OF TUMORIGENESIS
 PROJECT SUMMARY
 Ras GTPases represent a cancer-driving nexus that is difficult to target, underscoring the
need to better characterize the spectrum of Ras-interacting biomolecules that govern its
function. Using new methods designed to find previously missed interactors, recent CA142635
efforts defined the Ras RNA and protein interactomes to identify a functionally important
new RNA binding capacity for Ras as well as 38 new cancer-relevant Ras-interacting proteins.
Ras selectively and directly bound C/D box small non-coding RNAs snoRNAs, including
SNORD50A/B, which potently inhibited Ras and was deleted at high frequency co-occurantly
with RAS gene mutation in human cancer. Live-cell vicinal protein labeling followed by mass
spectrometry detected protein interactions missed in prior studies, among which were mTOR
and the putative palmitoyltransferase, ZDHHC5. This competing renewal will define the
function of these new Ras interacting RNA and proteins in Ras-driven tumorigenesis.
 First, we will further characterize SNORD50A/B snoRNA impacts on Ras as well as the role
of other newly discovered Ras-binding snoRNAs. Based on the finding that SNORD50A/B
snoRNAs block farnesyltransferase binding to Ras, we will define the global impact of
SNORD50A/B deletion on Ras protein-protein interactions to shed further light on the newly
discovered modulation of Ras by RNA. We will also systematically test the function of
additional Ras-binding RNAs on Ras-driven neoplasia, beginning with 6 snoRNAs that are
recurrently mutated at high frequency in human cancer. Aim I will test the hypotheses that
SNORD50A/B snoRNAs remodel the Ras protein interactome to regulate Ras signaling and
that additional Ras-binding snoRNAs alter Ras action in tumorigenesis.
 Second, we will characterize the newly identified Ras-mTOR interaction in tumorigenesis
and will define the functional importance of additional vicinal proteins to oncogenic Ras
function. We will define the domains on Ras isoforms and mTOR responsible for the observed
direct binding of Ras to mTOR, examine the impact of Ras-mTOR binding on mTORC1 vs
mTORC2 kinase activity and assess the impacts of disrupting Ras-mTOR binding on Ras-
driven tumorigenesis in vivo. We will also systematically delete 38 newly identified Ras
proximal proteins and quantify their impact on Ras-driven tumorigenesis. Aim II will test the
hypotheses that Ras-mTOR binding is functional in Ras-driven tumorigenesis and that
multiple newly identified Ras-interacting proteins impact Ras signaling outcomes in neoplasia.
 At the end of the proposed funding cycle, this effort will define the function of newly
identified Ras-binding RNAs and Ras-proximal proteins in Ras-driven tumorigenesis.
1

## Key facts

- **NIH application ID:** 9972868
- **Project number:** 5R01CA142635-10
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PAUL KHAVARI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,114
- **Award type:** 5
- **Project period:** 2010-12-10 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972868

## Citation

> US National Institutes of Health, RePORTER application 9972868, Regulators of Tumorigenesis (5R01CA142635-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9972868. Licensed CC0.

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