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p53 Regulates Metabolism by Both Transcription-Dependent and Transcription-Independent Functions.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	p53 Regulates Metabolism by Both Transcription-Dependent and Transcription-Independent Functions./
Author:	Sanford, Jack Douglas.
Description:	1 online resource (168 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 84-11, Section: B.
Contained By:	Dissertations Abstracts International84-11B.
Subject:	Molecular biology. -
Online resource:	click for full text (PQDT)
ISBN:	9798379556471

p53 Regulates Metabolism by Both Transcription-Dependent and Transcription-Independent Functions.
Sanford, Jack Douglas.

p53 Regulates Metabolism by Both Transcription-Dependent and Transcription-Independent Functions. - 1 online resource (168 pages)

Source: Dissertations Abstracts International, Volume: 84-11, Section: B.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2023.

Includes bibliographical references

Loss or improper regulation of p53 plays a role in the progression of most human cancers. Understanding the molecular mechanisms that mediate the regulation and activity of p53 can lead to the development of therapeutics that restore p53 activity or target p53 loss in cancer. p53 protein levels are regulated by the activity of MDM2 and MDMX. While MDM2 ubiquitinates p53, leading to its degradation, the role of MDMX is poorly understood. In Chapter 2, I Investigate MDMX in MDM2Y487A MEF cells, which have a mutation in the C-terminal tail of MDM2, rendering it unable to efficiently ubiquitinate p53. In this context, MDMX is essential for the regulation of p53 protein levels. These data expand on previous in vitro studies that show that the MDMX C-terminal tail complements the MDM2 C-terminal tail to suppress p53 expression. p53 suppresses tumorigenesis through both nuclear and cytoplasmic activities. While many of the nuclear activities are well defined, the cytoplasmic function of p53 is poorly understood. In Chapter 3, I examine a mutant mouse that has a bat-mimicking amino acid change in the p53 nuclear localization signal. This mutant mouse has increased levels of p53 in the cytoplasm, but normal p53 transcriptional activity. This mouse develops several metabolic phenotypes, showing that cytoplasmic p53 regulates metabolism in vivo. Furthermore, I identified a novel cytoplasmic function of p53, that p53 is able to bind lactate dehydrogenase (LDH) B and inhibit LDH enzymatic activity in a transcription-independent manner. Overall, the study identifies a role for cytoplasmic p53 in the regulation of metabolism that favors energy generation and storage.p53 has also been shown to regulate fatty acid oxidation through its nuclear transcription-factor activity. In Chapter 4, I identify a novel p53 target gene carnitine o-octanoyltransferase (CROT) that is upregulated by numerous cellular stresses. In this chapter, I show that, through p53 activation, cells are able to transactivate CROT in response to nutrient stress in order to increase oxidation of very long chain fatty acids in order to survive starvation conditions.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798379556471Subjects--Topical Terms:

583443
Molecular biology.
Subjects--Index Terms:

Human cancerIndex Terms--Genre/Form:

554714
Electronic books.

p53 Regulates Metabolism by Both Transcription-Dependent and Transcription-Independent Functions.
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