The role of P53 signaling pathway in aging and cancer
Creators: name: Zhao, Yuhan
Publisher: name: No Publisher Supplied
Year: 2018

description: Part I:p53 codon 72 SNP and agingp53 has dual functions on longevity. p53 plays a crucial role in tumor suppression to prevent early death due to cancer. However, constitutively increased p53 activity accelerates the decline of stem/progenitor cells’ self-renewal function, which leads to accelerated aging and a reduced lifespan. In humans, the role of p53 in aging and longevity has not been well established. As a haploinsufficient gene, p53 is under the tight regulation in cells. Attenuation of p53 function (even with only 2-fold change) contributes greatly to tumorigenesis. p53 codon 72 single nucleotide polymorphism (SNP) is a naturally occurring common SNP with a nucleotide change, which results in either an arginine (R72) or a proline (P72) at codon 72. p53 codon 72 SNPs can influence the activity of p53. The P72 allele is weaker than the R72 allele in inducing apoptosis and suppressing cellular transformation. However, it is unclear whether the change of p53 activity in humans by the functional SNP could impact longevity. A perspective cohort study with an aging human population showed that P72 allele is associated with longer survival despite its increased risk for cancer development (van Heemst et al., 2005). These findings strongly suggest that p53 activity is reversely associated with aging, and functional SNPs in the p53 pathway could impact upon the lifespan in humans. In this study, we employed a mouse model system with knock-in of the human p53 gene (Hupki) carrying either R72 or P72 SNP to investigate the impact of p53 codon 72 SNP upon longevity and its underlying mechanism. Mice with p53 P72 allele showed weaker transcriptional activity than the R72 allele toward a subset of p53 target genes, suggesting that these mice retain the function of p53 codon 72 SNP in humans. We found that although mice with p53 P72 have increased cancer risk compared to mice with p53 R72, those mice with p53 P72 who escaped tumor development have longer lifespans compared to mice with p53 R72 that do not develop tumors. Mice with p53 P72 displayed a delayed aging process compared to mice with p53 R72, including less reduced bone density, less decreased dermal thickness and better wound healing ability. We further compared the effects of p53 codon 72 SNPs on stem cell population and function as a possible mechanism that contributes to their differences in longevity. Compared to mice with p53 R72, mice with p53 P72 allele have a smaller number of long-term stem/progenitor cells and better self-renewal function during the aging process. Consistent results were observed when long-term stem cell’s ability of engraftment and repopulation was evaluated by bone marrow transplantation assay. Taken together, results from this study demonstrate that p53 codon 72 SNP has a direct impact on aging and longevity in vivo in mouse models, and strongly support the role of p53 in the regulation of stem/progenitor cells’ function and longevity.Part II:Mechanism of mutant p53 accumulation and gain-of-function (GOF) in tumorsp53 is the most frequently (~50%) mutated gene in human cancers. Besides the loss of tumor suppressive activity of wild-type p53 (wtp53), many tumor-associated mutant p53 (mutp53) proteins gain oncogenic functions to promote tumorigenesis, defined as gain-of-function (GOF). Mutp53 often accumulates to high levels in tumors, which is critical for mutp53 to exert GOF. The goal of this proposed research is to understand the mechanisms for mutp53 accumulation and GOF in tumors by identifying molecules that regulate mutp53 protein levels and functions, and furthermore, to develop potential intervention strategy targeting mutp53 accumulation and/or GOF. I searched for proteins interacting with mutp53 protein which may regulate mutp53 protein levels and/or GOF by immunoprecipitation combined with mass spectrometry screening in tumors from R172H mutp53 knock-in mice. Through this approach, we identified several novel mutp53- binding proteins, including Bcl-2-associated athanogene 2 (BAG2) and Pontin. BAG2 belongs to the BAG family and functions as a co-chaperone protein in cells. The expression level of BAG2 in cancers has been shown to associate with prognosis in cancer patients, including breast cancer and colon cancer. Results from our study suggest that BAG2 overexpression promotes mutp53 protein accumulation, which in turn contributes to mutp53 GOF in tumorigenesis. BAG2, a member of BAG family proteins, can bind to mutp53 through its BAG domain to disrupt mutp53-MDM2 interaction. Therefore, BAG2 promotes mutp53 accumulation through inhibiting MDM2-mediated mutp53 ubiquitination and degradation. It is possible to develop novel treatment strategies that targeting BAG2 to treat cancers with mutp53. Pontin, a highly conserved AAA+ ATPase, plays an important role in many cellular activities, including regulation of transcription, telomerase activity, chromatin remodeling, metabolism, and DNA repair. We identified Pontin as a novel mutp53-binding protein. The mutp53-Pontin interaction promotes mutp53 GOF in migration and invasion. Pontin promotes mutp53 GOF through regulation of mutp53 transcriptional activity; knockdown of Pontin abolished the transcriptional regulation of mutp53 toward a group of genes. Blocking the ATPase activity of Pontin by a Pontin-specific ATPase inhibitor or an ATPase-deficient dominant-negative Pontin expression vector greatly diminished mutp53 GOF. Therefore, identification of novel targetable mutant p53 interacting proteins will shed light on potential cancer therapeutic strategies, especially to tumors containing mutp53.