The functions of p53 are tightly regulated by an exquisite network of fine-tuning mechanisms that ensure proper responses to the various stress signals encountered by cells. In broad terms, p53 activities are controlled via protein levels, coactivator/corepressor recruitment, and a diverse array of post- translational. Numerous studies demonstrate that non-histone protein acetylation is critically involved in regulating diverse cellular processes. p53 was the first non-histone protein shown to be regulated functionally by acetylation and deacetylation and subsequent work has established that acetylation plays a key role in controlling promoter-specific activation of p53 targets during stress responses. The major acetylation sites of human p53 include two lysine residues (K120 and K164) within the DNA-binding domain and a cluster of six lysines with the C-terminal domain. To investigate whether p53 acetylation is important for tumor suppression, we generated p53-mutant mice (p53K117R/K117R) in which K117 (K120 in human) is replaced by arginine. In these animals, p53-mediated apoptosis is completely abrogated but p53- dependent cell cycle arrest and senescence remain intact. We also established mice (p533KR/3KR) in which the three acetylation sites of the DNA-binding domain (K117, K161, K162) were simultaneously replaced by arginine. Significantly, loss of acetylation at these three sites completely abolished the ability of p53 to mediate cell cycle arrest, apoptosis, and senescence in vivo. To evaluate whether these p53-dependent processes are required for tumor suppression, we monitored tumor formation in cohorts of p53 acetylation- deficient mice. Although p53-null mice rapidly develop spontaneous thymic lymphomas, neither p53K117R/K117R nor p533KR/3KR mice are prone to early-onset tumorigenesis. Since tumor suppression can be mediated by a p53 polypeptide (e.g., p533KR) that lacks the ability to induce p53-dependent cell cycle arrest, apoptosis, and senescence, these results indicate that other aspects of p53 function are sufficient to suppress tumor formation. Strikingly, the p533KR mutant retains the capacity to inhibit glycolysis and reduce the levels of reactive oxygen species (ROS). These findings suggest that current views regarding the mechanism of p53-mediated tumor suppression should be reconsidered. The main issues to be tested here are whether p53-mediated metabolic regulation of serine biosynthesis is critical for tumor suppression and that the metabolic targets of p53 are tightly controlled by oncoprotein Mdmx in tumorigenesis. The proposed studies include the following two specific aims.
In aim 1, we will dissect the molecular mechanisms of p53- mediated transcriptional program involving a new regulator of p53 UHRF1 as well as a novel p53 target PHGDH.
In Aim2, we will test whether the acetylation-defective mutant p533KR is still regulated by oncoprotein Mdmx and evaluate the physiological consequence of this regulation in mouse models.
By using these cells and tissues derived from p53 mutant mice, we will elucidate mechanisms of p53-mediated metabolic regulation in suppressing tumorigenesis. We will also test whether metabolic targets of p53 are regulated by Mdmx and evaluate the physiological consequence of this regulation in mouse models. This study will elucidate novel molecular mechanisms for p53-mediated tumor suppression and yield crucial insights regarding new pathways potentially targeted in cancer therapy.
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