# Defining USP22 Functions During Mammalian Development

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $407,798

## Abstract

Project Summary
Overexpression of the USP22 ubiquitin specific protease is linked to poor patient outcome in multiple types of
therapy resistant cancers, leading to its designation as a member of a `death from cancer' gene signature.
However, the functions of USP22 in normal cells are not well defined, so it is not clear how this enzyme
contributes to cancer formation or progression. USP22 is the catalytic subunit of the deubiquitination module
(DUB) within the highly conserved SAGA complex, which regulates multiple steps in the process of gene
transcription. In the last funding period, we generated USP22 null mice to further define its functions in vivo,
and we discovered a role for USP22 in development of fetal vasculature during development of the placental
labyrinth. RNA-seq reveals that TGF-beta and receptor tyrosine kinase (RTK) pathways (e.g. c-Met/HGFR,
Errb2, and PDGFR) are down regulated in USP22 mutant placentas. These pathways are essential not only
for normal placental development but also for tumorigenesis, and examination of TCGA data reveals that these
pathways are up regulated in tumors that overexpress USP22. We hypothesize that USP22 regulates these
pathways to control the growth and behavior of normal cells, and that aberrations in USP22 expression
contributes to signaling pathway aberrations associated with disease. To test this hypothesis and to define the
mechanistic basis of changes in TGF-beta and RTK signaling in Usp22 mutants, we will use mice and cells
bearing a conditional null, `floxed' allele or a conditional overexpressing allele of USP22 to 1) Define specific
cell lineages in the placenta affected by USP22 loss 2) Define direct molecular targets of USP22 and 3)
Determine whether USP22 overexpression is sufficient to drive abnormal TGF-beta1 or RTK signaling in mice.
These studies will establish new paradigms for the functions of USP22 in signaling, in development, and in
disease. In the longer term, our findings will provide new insights to the etiology of preeclampsia and cancer,
and they may provide new avenues for treatment or prevention of these conditions.

## Key facts

- **NIH application ID:** 9951077
- **Project number:** 5R01HD094400-07
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** SHARON Y. R. DENT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,798
- **Award type:** 5
- **Project period:** 2012-04-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951077

## Citation

> US National Institutes of Health, RePORTER application 9951077, Defining USP22 Functions During Mammalian Development (5R01HD094400-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9951077. Licensed CC0.

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