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

Award Number: R01CA203965
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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The role of chronic stress in regulation of mutant p53 and tumorigenesis - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Biology Research	000	5	10/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $363,306 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	5	12/8/2020	NON-COMPETING CONTINUATION	$345,140
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	001	5	1/25/2021	NON-COMPETING CONTINUATION	$18,166
														Subtotal = $363,306

Issue Date FY: 2020 ( Subtotal = $363,306 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	001	4	1/16/2020	NON-COMPETING CONTINUATION	$36,331
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	4	12/2/2019	NON-COMPETING CONTINUATION	$326,975
														Subtotal = $363,306

Issue Date FY: 2019 ( Subtotal = $352,406 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	3	12/18/2018	NON-COMPETING CONTINUATION	$352,406
														Subtotal = $352,406

Issue Date FY: 2018 ( Subtotal = $363,306 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	2	12/5/2017	NON-COMPETING CONTINUATION	$326,975
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	001	2	5/23/2018	NON-COMPETING CONTINUATION	$36,331
														Subtotal = $363,306

Issue Date FY: 2017 ( Subtotal = $363,306 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	1	12/2/2016	NEW	$363,306
														Subtotal = $363,306

Grand Total All Awards = $1,805,630

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

Award Number: R01CA203965

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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