The p53 tumor suppressor gene is best known as the most frequently mutated gene in human cancer. Consequently, elucidation of the p53-dependent tumor suppressive pathway remains a fundamental area of cancer research. To date, few studies have addressed the possibility that coding region polymorphisms in p53 can alter the apoptotic and tumor suppressive functions of this protein. Our preliminary data suggest that two polymorphisms that exist in p53, a common polymorphism at codon 72 and a rarer one at codon 47, can both alter the ability of p53 to induce programmed cell death. Specifically, we have found that the codon 72 arginine variant (R72), which has been the subject of very few studies, has fifteen-fold increased ability to induce apoptosis. At least part of this increased apoptotic ability relies on an increased association of this protein with the ubiquitin ligase MDM2, which catalyzes the nuclear export of p53. As a consequence of increased nuclear export, we show that the R72 variant demonstrates enhanced localization to mitochondria, where we show that it can directly bind and oligomerize the pro-apoptotic protein BAK. At codon 47, p53 can encode either proline (wild type) or serine; S47 has been detected in less than 5 percent of African Americans. We show that the S47 variant has decreased apoptotic ability, due in part to altered phosphorylation of serine 46, as well as reduced ability to transactivate the p53-response gene PUMA. To date, the functional significance of p53 polymorphic variants to cancer risk, and the efficacy of therapy, has never been elucidated. We propose to create mouse models for each variant, and test their ability to suppress tumor development and induce apoptosis. Additionally, the contribution of the mitochondrial p53 pathway has never been determined. Using our insight from studies on the codon 72 polymorphism, we propose to determine this contribution. ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Etiology Study Section (CE)
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Blair, Donald G
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Fox Chase Cancer Center
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Basu, Subhasree; Murphy, Maureen E (2016) Genetic Modifiers of the p53 Pathway. Cold Spring Harb Perspect Med 6:a026302
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
Kung, Che-Pei; Murphy, Maureen E (2016) The role of the p53 tumor suppressor in metabolism and diabetes. J Endocrinol 231:R61-R75
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Kung, Che-Pei; Basu, Subhasree; Murphy, Maureen E (2016) A link between TP53 polymorphisms and metabolism. Mol Cell Oncol 3:e1173769
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Murphy, Maureen E (2016) Ironing out how p53 regulates ferroptosis. Proc Natl Acad Sci U S A 113:12350-12352
Basu, Subhasree; Barnoud, Thibaut; Kung, Che-Pei et al. (2016) The African-specific S47 polymorphism of p53 alters chemosensitivity. Cell Cycle 15:2557-2560
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

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