# Mechanisms of targeting oncoprotein SET in tumor suppression

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $366,000

## Abstract

Project Summary
 The oncoprotein Mdm2 acts as a key factor in suppressing p53 tumor suppressor in human cancer cells
and inhibition of Mdm2 function is a validated approach to restore p53 function for cancer therapy. Nevertheless,
inhibitors of Mdm2 such as Nutlin-3 have certain limitations, suggesting that additional targets in this pathway
need to be further elucidated. The proposed studies aim to dissect the mechanisms of one newly-identified
oncoprotein SET in controlling p53-mediated tumor suppression and provide the unequivocal evidence as “proof
of concept” for targeting SET in cancer therapy. Inactivation of the p53 tumor suppression pathway is a pivotal
event in the formation of most human cancers. To further elucidate the precise mechanisms of p53 regulation in
human cancers, we have identified SET as a novel p53-binding protein whose interactions with p53 are totally
dependent on its C-terminus. The oncoprotein SET was initially identified from an oncogenic fusion-protein SET-
CAN resulted from chromosome translocation in several types of leukemia. Interestingly, the SET-p53 interaction
is specifically regulated by the status of the C-terminal acetylation. In our preliminary studies, we found that SET
acts as a transcriptional corepressor and inhibits p53-mediated transcriptional activation. SET strongly interacts
with unacetylated p53 through its C-terminus; however, upon acetylation at those C-terminal lysine residues, the
p53-SET interaction is completely abrogated, which leads to activation of p53 functions. The central hypothesis to
be tested here is whether the activities of p53 are tightly controlled by SET in human cancer cells and whether
inactivation of SET leads to p53 activation and tumor regression in vivo. The proposed studies include the
following two specific aims. In Aim 1, we will perform Mechanistic studies of the SET-p53 interplays in
suppressing p53 function and the roles of SET in p53-mediated cell growth repression of human cancer cells. In
Aim 2, we will test whether p53 is regulated by SET in vivo and evaluate the physiological significance of the
SET-p53 interaction in mouse tumor models.

## Key facts

- **NIH application ID:** 9889054
- **Project number:** 5R01CA216884-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Wei Gu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889054

## Citation

> US National Institutes of Health, RePORTER application 9889054, Mechanisms of targeting oncoprotein SET in tumor suppression (5R01CA216884-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9889054. Licensed CC0.

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