This is a competing renewal application for the continuation of my first funded R01 since 2000, which has allowed us to establish the crucial role for p53 acetylation in modulating its activities. Notably, our findings have had important implications well beyond p53 biology. Since our discovery of p53 acetylation, over 3600 lysine acetylation sites have been identified on more than 1750 human proteins. For example, the methods and concepts developed in our studies have been applied to numerous other cellular proteins and laid the foundation for the current view that reversible acetylation is a general mechanism for regulation of non-histone proteins. Inactivation of the p53 tumor suppressor is a pivotal event in the formation of most human cancers. p53 plays a central role by acting as a transcription factor to modulate cell growth, cell death and metabolism. Numerous studies including ours have demonstrated that acetylation of p53 is critically involved in transcriptional activation and tumor suppression. The major acetylation sites of human p53 include lysine residues within the DNA-binding domain and a cluster of lysine residues within its C-terminal domain (CTD). Nevertheless, the mechanisms of acetylation-mediated actions are not completely understood. Lysine acetylation often creates binding sites for ?reader? proteins such as bromodomain-containing proteins; surprisingly, in a proteomic screen for the binding proteins of both unacetylated and acetylated p53, we have recently discovered that the acidic domain acts as a new ?reader? for acetylated p53. These results reveal that the acidic domain-containing factors such as VprBP act as a new class of acetylation-dependent regulators critically involved in p53 regulation. The central hypothesis to be tested here is whether acetylation-mediated regulation of p53 is crucial for its stability control and promote-specific activation of target genes for tumor suppression.
In Aim 1, we will dissect the mechanisms by which p53 stability is controlled through the cross talk between acetylation and ubiquitination pathways.
In Aim2, we will investigate the role of acetylation in transcription and tumor growth suppression by using a knockin mouse model expressing an acetylation-mimicking form (K-Q) of p53.
Despite the fact that acetylation has been well accepted as a major mechanism for activating p53 in the field, the precise mechanisms of acetylation-mediated actions are not well understood. We have identified VprBP as a critical factor for acetylation-mediated regulation. By using both tissue culture and animal models, we will test whether the mechanisms of acetylation-mediated functions as well as its significance in tumor suppression.
| Kon, Ning; Wang, Donglai; Li, Tongyuan et al. (2018) Inhibition of Mdmx (Mdm4) in vivo induces anti-obesity effects. Oncotarget 9:7282-7297 |
| Li, Dawei; Tavana, Omid; Sun, Shao-Cong et al. (2018) Peli1 Modulates the Subcellular Localization and Activity of Mdmx. Cancer Res 78:2897-2910 |
| Tavana, Omid; Sun, Hongbin; Gu, Wei (2018) Targeting HAUSP in both p53 wildtype and p53-mutant tumors. Cell Cycle 17:823-828 |
| Tavana, Omid; Gu, Wei (2017) Modulation of the p53/MDM2 interplay by HAUSP inhibitors. J Mol Cell Biol 9:45-52 |
| Chen, Delin; Tavana, Omid; Chu, Bo et al. (2017) NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression. Mol Cell 68:224-232.e4 |
| Wang, Donglai; Kon, Ning; Gu, Wei (2016) Acidic domains: ""converse readers"" for acetylation code. Oncotarget 7:80101-80102 |
| Ou, Yang; Wang, Shang-Jui; Li, Dawei et al. (2016) Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci U S A 113:E6806-E6812 |
| 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 |
| Tavana, Omid; Li, Dawei; Dai, Chao et al. (2016) HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nat Med 22:1180-1186 |
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