There is accumulating evidence indicating that p53 is critical in regulation of glycolysis, reactive oxygen species (ROS) production and oxidative stress responses under normal physiological conditions. A number of studies showed that loss of p53 results in decreased mitochondrial respiration and enhanced glycolysis, leading to the Warburg effect. p53 also induces several antioxidant genes, including TIGAR and GLS2, to reduce the levels of reactive oxygen species (ROS). Notably, ROS production causes DNA damage through oxidation of nucleotide bases by increasing 8-hydroxy-22-deoxyguanosine (8-OH-dG) levels. Thus, antioxidant activities of p53 are involved in limiting DNA damage through reducing ROS levels. Nevertheless, it remains unclear whether this part of p53 functions directly contributes to the role of p53 as a tumor suppressor. We have recently demonstrated that acetylation of p53 is required for its activation of cell cycle arrest and apoptosis. In our preliminary studies, we have generated mice bearing lysine to arginine mutations at one (p53K117R) or three (p533KR; K117R+K161R+K162R) of the critical p53 acetylation sites. While p53K117R/K117R cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p533KR/3KR cells. Surprisingly, unlike p53-null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in either p53K117R/K117R or p533KR/3KR animals. Since p533KR/3KR mice lack p53-mediated cell cycle arrest, apoptosis, and senescence, this observation suggests that other aspects of p53 function are sufficient for suppression of early-onset tumorigenesis. Notably, p533KR retains the ability to transactivate metabolic target genes, such as TIGAR and GLS2, and subsequently suppresses glycolysis and reactive oxygen species (ROS) production. The central hypothesis to be tested here is whether p53-mediated effects in glycolysis, ROS production and oxidative stress responses act as an independent mechanism in tumor suppression in the absence of cell-cycle arrest, apoptosis and senescence. The proposed studies include the following two specific aims.
In Aim 1, we will dissect the role of p53 in regulating reactive oxyge species (ROS) production, oxidative stress responses and glycolysis, in the absence of cell cycle arrest, apoptosis and senescence.
In Aim 2, we will examine whether p53 mediated effects on reactive oxygen species (ROS) production, DNA oxidation damage and glycolysis are critical in suppressing oncogene-mediated tumorigenesis.

Public Health Relevance

There is accumulating evidence indicating that p53 is critical in regulation of glycolysis, reactive oxygen species (ROS) production and oxidative stress responses under normal physiological conditions. Nevertheless, it remains unclear whether this part of p53 functions directly contributes to the role of p53 as a tumor suppressor. We have recently demonstrated that cell cycle arrest, senescence and apoptosis are not absolutely required for tumor suppression. Furthermore, we found that p53-mutant mice lack p53-mediated cell cycle arrest, apoptosis, and senescence but retain the ability to regulate glycolysis and reactive oxygen species (ROS) production. By using these p53-mutant mice, we will test whether p53-mediated effects in glycolysis, ROS production and oxidative stress responses act as an independent mechanism in tumor suppression in the absence of cell-cycle arrest, apoptosis and senescence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA172023-05
Application #
9120343
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Watson, Joanna M
Project Start
2012-09-26
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Shi, D; Dai, C; Qin, J et al. (2016) Negative regulation of the p300-p53 interplay by DDX24. Oncogene 35:528-36
Wang, Shang-Jui; Li, Dawei; Ou, Yang et al. (2016) Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression. Cell Rep 17:366-373
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Jiang, Le; Kon, Ning; Li, Tongyuan et al. (2015) Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520:57-62
Jiang, Le; Hickman, Justin H; Wang, Shang-Jui et al. (2015) Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses. Cell Cycle 14:2881-5
Ou, Yang; Wang, Shang-Jui; Jiang, Le et al. (2015) p53 Protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation. J Biol Chem 290:457-66
Qiang, Li; Kon, Ning; Zhao, Wenhui et al. (2015) Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions. Cell Rep 11:1797-808
Yi, Jingjie; Huang, Xiangyang; Yang, Yuxia et al. (2014) Regulation of histone acetyltransferase TIP60 function by histone deacetylase 3. J Biol Chem 289:33878-86

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