The central importance of the p53 tumor suppressor gene to human cancer research is best epitomized by the following facts: 1) p53 is the most frequently mutated gene in human cancer;2) p53 is a central signaling molecule in DNA damage-mediated apoptosis;3) tumors with mutations in p53 have universally poor prognosis. Much is currently known regarding the molecular basis for p53's tumor suppressor function;tumor suppression by this protein is mediated by its ability to induce growth arrest, senescence and apoptosis. p53 is best characterized as a sequence-specific transcription factor, and it elicits growth arrest primarily through transactivation of the cyclin-dependent kinase inhibitor p21/waf1. In order to induce death p53 transactivates pro-apoptotic target genes such as the BH3-only proteins PUMA and NOXA;p53 also has a direct apoptogenic role at the mitochondria. While a great deal is understood about how p53 functions as a tumor suppressor, remarkably little is known about how coding region polymorphisms in p53 impact these functions. There are three polymorphic variants of p53. A common polymorphism exists at codon 72, encoding either arginine (R72) or proline (P72). Work from our group and others has shown that the R72 form of p53 has markedly increased apoptotic function, due to increased ability to localize to mitochondria and transactivate the p53 target gene PERP. At codon 47, p53 encodes proline (wild type) or serine (S47). We have found the S47 variant has decreased phosphorylation on serine 46, and up to three-fold decreased apoptotic function due to impaired ability to transactivate PUMA. Therefore, in terms of apoptosis, R72 >P72 >S47. The long-term objective of proposed research is to use mouse models for p53 polymorphic variants in order to dissect the different mitochondrial and transcriptional functions of these variants in the context of a living organism. An added goal is to use our P72, R72 and S47 mice in order to more accurately assess the impact of these variants on cancer progression and the efficacy of cancer therapy in mouse models of lymphoma and colorectal cancer. The lesser-apoptotic P72 and S47 variants are significantly more common in African Americans. Therefore these studies will be important for understanding (and eventually eliminating) disparities in cancer risk and prognosis in underserved populations, which is one goal of the NIH roadmap.

Public Health Relevance

Published data from our group and others indicate that there are three coding region variants of the p53 protein in human populations, and further that these three variants all have significant differences in p53 function. Whereas a great deal is known about how p53 functions to suppress cancer, to date very little is known about how these polymorphic variants of p53 influence cancer risk or the efficacy of therapy;the proposed research will directly address this question. Because the two lesser-functioning variants (S47 and P72) are both more common in African Americans, data generated from this study has direct relevance to understanding the differences in cancer risk and prognosis in this population.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102184-08
Application #
8403786
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Hildesheim, Jeffrey
Project Start
2003-07-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
8
Fiscal Year
2013
Total Cost
$302,498
Indirect Cost
$126,627
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Murphy, Maureen E; Liu, Song; Yao, Song et al. (2017) A functionally significant SNP in TP53 and breast cancer risk in African-American women. NPJ Breast Cancer 3:5
Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285
Murphy, Maureen E (2016) Ironing out how p53 regulates ferroptosis. Proc Natl Acad Sci U S A 113:12350-12352
Kung, Che-Pei; Basu, Subhasree; Murphy, Maureen E (2016) A link between TP53 polymorphisms and metabolism. Mol Cell Oncol 3:e1173769
Kung, Che-Pei; Leu, Julia I-Ju; Basu, Subhasree et al. (2016) The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction. Cell Rep 14:2413-25
Basu, Subhasree; Murphy, Maureen E (2016) p53 family members regulate cancer stem cells. Cell Cycle 15:1403-4
Jennis, Matthew; Kung, Che-Pei; Basu, Subhasree et al. (2016) An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev 30:918-30
Tutton, Stephen; Azzam, Greggory A; Stong, Nicholas et al. (2016) Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres. EMBO J 35:193-207
Basu, Subhasree; Murphy, Maureen E (2016) Genetic Modifiers of the p53 Pathway. Cold Spring Harb Perspect Med 6:a026302

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