# Cell lineage determinants of p53-driven fate outcomes in vivo

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $576,567

## Abstract

PROJECT SUMMARY
Mutation of the TP53 gene is frequent in human cancer with wild-type p53 clearly being implicated as a tumor
suppressor. A growing body of evidence now supports the notion that tumor-associated mutant p53 has not only
lost tumor suppressing activity, but has also gained oncogenic roles. Thus, a central and significant challenge is
to elucidate the molecular bases both for the tumor suppressing functions of wild-type p53 and the oncogenic
activities of mutant p53 as well as deconvoluting the molecular relationship between these two. It is reasonable
to expect that relevant detailed insights into wild-type-mediated tumor suppression will inform understanding of
mutant-driven oncogenesis and vice versa. It is further hypothesized that by studying wild-type and mutant p53
in parallel, insights will be gained that would have been otherwise elusive. Further confounding this complex
question, studies using mouse models in vivo indicate that p53-driven cell fate outcomes, be they tumor
suppressing or oncogenic, can be tissue-specific. Although p53 has been shown to have cytoplasmic functions,
its role in controlling gene expression is certainly central to both its wild-type tumor suppressing role and its
mutant oncogenic function. The goal of the planned studies is to address this significant issue which carries
important translational potential. Specific aims are proposed to explore the tissue-specific transcriptional activity
of either wild-type or mutant p53 in vivo and to identify lineage-specific determinants for p53-driven fate outcomes
in a subset of tissues, namely, liver, thymus, and spleen. The first aim is focused on wild-type p53 in vivo and
involves elucidating the molecular basis for cell lineage as a determinant for the wild-type p53-dependent
response to DNA damage. The second aim deals with tumor-associated mutant p53 and is to explore the
molecular basis for the tissue-specific oncogenic activity of mutant p53. Given the essential role of transcriptional
regulation in the activity of p53, it is postulated that downstream control of specific target genes are key
determinants of cellular outcomes. Elucidating the molecular basis for the tumor suppressor activity of wild-type
p53 is essential to be able to exploit such findings as a means to restore this function in tumor cells as a
therapeutic approach. Likewise, the existence of gained oncogenic activity by tumor-associated mutant p53
provides the unexpected possibility for a targeted therapy involving a tumor suppressor. As a key difference
between normal and tumor cells is their p53 status, it is anticipated that such approaches are likely to have a
high therapeutic index. Given the tissue-specificity of responses to p53, it is essential that studies of p53-driven
fate outcomes be addressed in a cell lineage-dependent manner, providing a central tenet for the proposed
research.

## Key facts

- **NIH application ID:** 10316263
- **Project number:** 5R01CA257548-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** James J Manfredi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $576,567
- **Award type:** 5
- **Project period:** 2020-12-09 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316263

## Citation

> US National Institutes of Health, RePORTER application 10316263, Cell lineage determinants of p53-driven fate outcomes in vivo (5R01CA257548-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10316263. Licensed CC0.

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