# Modulation of wild type and mutant p53 by HMGA1

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2020 · $67,446

## Abstract

PROJECT ABSTRACT
Inactivation of the p53 tumor suppressor is essential for oncogenesis. My preliminary data indicate that p53
mutants that retain DNA binding capacities (ie p53 R282W) mediate oncogenesis through distinct
transcriptional mechanisms compared to other p53 mutants. p53 R282W binds chromatin at canonical p53
sites, yet does not activate canonical p53 targets. Instead, p53 in R282W-containing cell lines activates gene
neighbors of canonical p53 targets, as well as genes that reside in clusters in the genome. Critically, p53 in
mutant cells drives expression of the HMGA1, a cancer-associated DNA-bending factor that facilitates
chromatin looping. I propose a model in which HMGA1 modifies p53 activity by inducing p53 target-switching
and long-range gene activation, and by driving p53 genomic recruitment to AT-rich p53 response elements,
which are preferentially bent by HMGA1. I hypothesize that HMGA1 modulates the activity of wild type and
mutant p53 through similar mechanisms. However, based on the lower affinity of p53 mutants for DNA, I
predict that HMGA1 will have more pronounced effects on genomic recruitment of mutant p53. This work has
the potential to transform our understanding of p53 biology by demonstrating a unifying mechanism by which
wild type and mutant p53 are hijacked to promote cancer.

## Key facts

- **NIH application ID:** 9938476
- **Project number:** 5F32CA221010-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Katherine Ann Alexander
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938476

## Citation

> US National Institutes of Health, RePORTER application 9938476, Modulation of wild type and mutant p53 by HMGA1 (5F32CA221010-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9938476. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*