# Project 1: Roles of wild-type and mutant forms of p53 in cancer cell biology

> **NIH NIH P01** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2020 · $338,838

## Abstract

Project Summary
Project 1: Opposing Roles of Wild-type and Mutant p53 in Regulating Oncogenesis.
The wild-type p53 protein is recognized as a major tumor suppressor protein. p53 sits at the
hub of numerous upstream stress signaling and downstream gene regulatory pathways and
works as a transcription factor whose varied transcriptional targets mediate numerous cellular
outcomes. Depending on the context, these include cell cycle, cell death, senescence,
metabolic changes and others that serve to protect cells from acquiring cancerous properties.
By contrast, evidence continues to mount that the common mutant forms of p53 found in human
tumors are actually contributing to their malignant properties. Both wild-type and mutant p53
have been shown to regulate expression over 1000 genes each. Interestingly, in many cases
the genes and pathways that mutant p53 upregulates are actively inhibited by wild-type p53.
One line of evidence for mutant p53 gain of oncogenic function that was supported by this
program was the discovery that mutant p53 regulates the SREBP-2-dependent mevalonic acid
(MVA) pathway by which cells synthesize cholesterol and that this is required for the malignant
characteristics of breast cancer cells grown in 3D cultures. We now have evidence in
collaboration with the Lowe laboratory that wild-type p53 actively represses the MVA pathway
by a novel mechanism whereby p53 induces the ABCA1 cholesterol exporter leading to blocked
maturation of the SREBP-2 transcription factor. With Scott Lowe we showed that p53
repression of the MVA pathway is required for Myc/p53 null liver tumors to develop.
Interestingly, a key byproduct of the MVA pathway, namely protein geranylgeranylation, is
required for mutant p53 to upregulate the MVA pathway and ablation of this byproduct plays a
role in wild-type repression of this pathway. We also recently discovered VEGFR2, the receptor
for the pro-angiogenic VEGF ligand, as another gene that is up-regulated by mutant p53 in
breast cancer cells. Activation of VEGFR2 RNA expression involves mutant p53 cooperation
with the SWI/SNF chromatin remodeling complex. Indeed, mutant p53 regulation of nearly half
of its targets including the MVA pathway genes requires SWI/SNF. The goals of this project are
to gain further insight into how mutant p53 works with SREBP2 to regulate both known (MVA
and VEGFR2) as well as anticipated new target genes, to gain insight into the positive feedback
relationship between mutant p53 and SWI/SNF, to determine how and when p53 activates
ABCA1 to block maturation of the SREBP2 protein, to identify which geranylgeranyl targets are
required for maintaining growth and malignancy in breast cancer cell cultures, and to identify
factors that lead to dependency on the MVA pathway for viability. These experiments, which will
potentially inform new treatments for cancer, will in many cases involve collaborative projects
with the other members of this program.

## Key facts

- **NIH application ID:** 9905335
- **Project number:** 5P01CA087497-19
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** Carol Prives
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,838
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905335

## Citation

> US National Institutes of Health, RePORTER application 9905335, Project 1: Roles of wild-type and mutant forms of p53 in cancer cell biology (5P01CA087497-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9905335. Licensed CC0.

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