# The role of chronic stress in regulation of mutant p53 and tumorigenesis

> **NIH NIH R01** · RBHS -CANCER INSTITUTE OF NEW JERSEY · 2021 · $363,306

## Abstract

Epidemiological studies strongly suggest that chronic stress has significant negative influences on the
onset, progression and mortality of human tumors. However, the role and underlying mechanisms of chronic
stress in tumorigenesis remain elusive. Employing chronic restraint in mice, a well-established mouse model
to induce chronic stress, we found that chronic stress promotes IR-induced lymphoma formation in mice.
Tumor suppressor p53 and its signaling pathway play a critical role in tumor suppression. Our recent studies
found that chronic restraint greatly decreases wild type p53 (wtp53) protein levels and function, which is an
important mechanism by which chronic stress promotes tumorigenesis in tumors containing wtp53. p53 is
the most frequently-mutated gene in human tumors; over 50% of all tumors harbor p53 mutations. Many
tumor-associated mutant p53 (mutp53) proteins not only lose the tumor suppressive function of wtp53, but
also gain new activities to promote tumorigenesis, defined as gain-of-function (GOF). Mutp53 proteins often
accumulate to high levels in tumors which is critical for mutp53 GOF. Interestingly, our preliminary data show
that chronic stress promotes mutp53 protein accumulation and GOF in tumorigenesis. Chronic stress results
in the prolonged elevation of catecholamines, which activates -adrenergic receptor ( -AR) and its signaling
to mediate many effects of chronic stress. Our preliminary studies suggest that catecholamines mediate the
promoting effect of chronic stress on mutp53 protein accumulation and GOF. Based on our preliminary
studies, we hypothesize that chronic stress promotes tumorigenesis, and the up-regulation of mutp53
protein levels and GOF in tumorigenesis by catecholamines is an important underlying mechanism
for tumors containing mutp53. In this proposed study, we will 1) test the hypothesis that chronic stress
preferentially promotes tumorigenesis in tumors containing mutp53 through promoting mutp53 accumulation
and GOF by employing mouse tumor models; 2) test the hypothesis that the up-regulation of mutp53 protein
levels and GOF by catecholamines is an important mechanism by which chronic stress promotes
tumorigenesis in tumors containing mutp53; 3) determine the mechanisms by which catecholamines promote
mutp53 accumulation and GOF. We expect that this study will provide direct evidence that chronic stress
promotes tumorigenesis of mutp53 containing tumors, and validate that the up-regulation of mutp53 protein
levels and GOF by catecholamines is an important mechanism. Blocking chronic stress and/or -AR
signaling could be a novel therapeutic strategy for mutp53 containing tumors. This study has the potential to
provide pivotal molecular targets for disrupting stress/neurohormone signaling in the tumor microenvironment
to treat undruggable mutp53 containing tumors.

## Key facts

- **NIH application ID:** 10064131
- **Project number:** 5R01CA203965-05
- **Recipient organization:** RBHS -CANCER INSTITUTE OF NEW JERSEY
- **Principal Investigator:** Wenwei Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $363,306
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064131

## Citation

> US National Institutes of Health, RePORTER application 10064131, The role of chronic stress in regulation of mutant p53 and tumorigenesis (5R01CA203965-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10064131. Licensed CC0.

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