Recently, they have demonstrated, for the first time, that the p53 tumor suppressor can be acetylated both in vitro and in vivo. The studies proposed in this application will test the hypotheses that acetylation/deacetylation of p53 is one of key events for p53 activation in response to DNA damage. It is well established that p53 exerts anti-proliferative effects, including growth arrest and apoptosis, in response to various types of stress such as DNA damage. They have previously found that CBP/p300, acting as a coactivator for p53, can dramatically stimulate p53-mediated transcriptional activity. They have further demonstrated that p53 is a bona fide substrate for p300 acetyltransferase function, and that the acetylation of p53 can strongly enhance its sequence-specific DNA binding activity. Recently, they have identified a functional deacetylase complex for p53 and the p53 target protein in this deacetylase complex (PID) has further been purified and cloned. Since acetylation of p53 can been enhanced in response to DNA damage, a novel pathway for p53 activation involving protein acetylation/deacetylation is proposed. The first specific aim is to demonstrate p53 acetylation in vivo and its functional consequence. Several acetylated p53 specific antibodies will be developed to monitor the regulation of p53 acetylation in vivo. The functional effects on in vivo sequence-specific DNA binding and transcriptional activation of p53 by acetylation in vivo. The functional effects on in vivo sequence-specific DNA binding and transcriptional activation of p53 by acetylation will also be addressed. They will investigate the regulation of p53 deacetylation and its functional consequence by PID.
The third aim i s to define the physiological function of PID in tumorigenesis. They will use both genetics and molecular biology approaches to test the role of PID in the regulation of p53-dependent cell growth inhibition and apoptosis.
| 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 |
| 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 |
| Wang, Donglai; Kon, Ning; Lasso, Gorka et al. (2016) Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Nature 538:118-122 |
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