The p53 tumor suppressor functions to transmit signals from myriad sources of cellular stress to genes and factors that control cell cycle, cell death and other cellular responses. The objective of the requested extension of this Merit Award is to extend and develop discoveries made during the previous period. The overall goal of the? proposed research is to characterize the regulation of p53 and how this regulation affects its functions in cells. ? (1) It is planned to focus extensively on the upstream component of the p53 pathway, with the goals of elucidating novel signaling pathways to p53 initiated by various forms of stress signals. It is planned to further delve into the role of phosphorylation of p53 in interacting with and regulation by Mdm2. The mechanism by which p53 is transcriptionally impaired when S phase is arrested will be sought.? (2) It is hoped to gain further insight into the mechanism by which non-covalent modifiers of p53, specifically Ref-1, HMG1 and HnRNP-U serve as transcriptional co-factors for p53. ? (3) The recent discovery that cyclin G interacts with phosphatase 2A and Mdm2 and thereby serves as a negative regulator of p53 will be extended in several directions including determining how these interactions are controlled under various circumstances in cells.? (4) The in vivo relevance of possible non-transcriptional roles of p53 in DNA repair and DNA synthesis will be determined.? ? NEW Aims? (1) To elucidate the mechanism and consequences of stress induced phosphorylation of p53 and Mdm2? (2) To determine how p53 becomes altered and impaired as a transcriptional activator when DNA synthesis is blocked.? (3) To examine the roles of non-covalent modifiers in regulation of transactivation by p53.? (4) To elucidate the role of the cyclin G family in regulation of p53 and Mdm2.? (5) To examine the relationship between p53 and DNA repair?
| Rokudai, Susumu; Li, Yingchun; Otaka, Yukihiro et al. (2018) STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis. Proc Natl Acad Sci U S A 115:E4806-E4814 |
| Katz, Chen; Low-Calle, Ana Maria; Choe, Joshua H et al. (2018) Wild-type and cancer-related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers. Genes Dev 32:430-447 |
| Lessel, Davor; Wu, Danyi; Trujillo, Carlos et al. (2017) Dysfunction of the MDM2/p53 axis is linked to premature aging. J Clin Invest 127:3598-3608 |
| Karni-Schmidt, Orit; Lokshin, Maria; Prives, Carol (2016) The Roles of MDM2 and MDMX in Cancer. Annu Rev Pathol 11:617-44 |
| Daftuar, Lilyn; Zhu, Yan; Jacq, Xavier et al. (2013) Ribosomal proteins RPL37, RPS15 and RPS20 regulate the Mdm2-p53-MdmX network. PLoS One 8:e68667 |
| Zhu, Yan; Regunath, Kausik; Jacq, Xavier et al. (2013) Cisplatin causes cell death via TAB1 regulation of p53/MDM2/MDMX circuitry. Genes Dev 27:1739-51 |
| Bursa?, Sladana; Brdov?ak, Maja Cokari?; Pfannkuchen, Martin et al. (2012) Mutual protection of ribosomal proteins L5 and L11 from degradation is essential for p53 activation upon ribosomal biogenesis stress. Proc Natl Acad Sci U S A 109:20467-72 |
| Biderman, Lynn; Poyurovsky, Masha V; Assia, Yael et al. (2012) MdmX is required for p53 interaction with and full induction of the Mdm2 promoter after cellular stress. Mol Cell Biol 32:1214-25 |
| Poyurovsky, Masha V; Katz, Chen; Laptenko, Oleg et al. (2010) The C terminus of p53 binds the N-terminal domain of MDM2. Nat Struct Mol Biol 17:982-9 |
| Priest, Christina; Prives, Carol; Poyurovsky, Masha V (2010) Deconstructing nucleotide binding activity of the Mdm2 RING domain. Nucleic Acids Res 38:7587-98 |
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