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.
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.
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