# 3'UTR-dependent regulation of the PTEN tumor suppressor gene

> **NIH NIH F31** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $46,036

## Abstract

Project Summary
PTEN, encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is a tumor
suppressor gene mutated in a variety of human cancers. However, unlike other tumor suppressor
genes, even small perturbations in PTEN activity can promote tumorigenesis suggesting it is highly
regulated. Post-translational regulation of PTEN can affect protein stability, localization, and
conformation as well as phosphatase activity, and in many cases the effects are cell type specific.
Our lab has observed that PTEN translated from the long 3'UTR isoform is significantly less active
in the PI3K pathway than PTEN translated from the short 3'UTR isoform, and that the expression
of 3'UTR isoforms varies across tissue and cell types. The goal of the proposed study is to
elucidate the molecular mechanism of 3'UTR-dependent regulation of PTEN activity to augment
our understanding of disease mechanisms in PTEN dysregulated cancers. The proposal has two
specific aims. Aim 1 will investigate the biological consequence of 3'UTR-dependent PTEN
regulation. Since there is no observed difference in PTEN protein levels in cells that predominantly
express the long 3'UTR isoform compared to cells that predominantly express the short 3'UTR
isoform, the hypothesis is that alternative isoform usage must effect either subcellular
localization, homo-dimerization, or phosphatase activity. Exclusive shRNA-mediated
knockdown of the long 3'UTR isoform will be used to generate cells that predominantly express the
short 3'UTR, which will be compared to control cells that express both isoforms equally. The cell
lines will be immunostained for endogenous PTEN and subcellular localization can be compared.
They will also be used to immunoprecipitate protein translated from primarily the short 3'UTR and
protein translated from both isoforms to assess how dimerization and phosphatase activity is
affected by alternative 3'UTR isoform usage. In Aim 2, these cell lines will be used to identify
protein factors that specifically interact with the long 3'UTR isoform. The hypothesis is that the
long 3'UTR of PTEN recruits a protein that forms a complex with newly translated PTEN,
thus repressing its activity in the PI3K pathway. Long 3'UTR-specific protein interaction
partners will be identified by mass spectrometry and the information obtained in Aim 1 will be
leveraged to select candidates to validate for their role in regulating PTEN protein. shRNA will be
used to knockdown candidate interaction partners. If a candidate is required for 3'UTR-dependent
PTEN regulation, then shRNA-mediated knockdown of this candidate will restore activity of PTEN
translated from the long 3'UTR isoform to that of PTEN translated from the short 3'UTR isoform.

## Key facts

- **NIH application ID:** 10212969
- **Project number:** 5F31CA254335-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ellen Horste
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212969

## Citation

> US National Institutes of Health, RePORTER application 10212969, 3'UTR-dependent regulation of the PTEN tumor suppressor gene (5F31CA254335-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212969. Licensed CC0.

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