A key negative regulator of the p53 tumor suppressor protein is Mdm2, a protein which can both suppress p53 transcriptional activation of its target genes and induce proteasomal degradation of p53. MdmX, the Mdm2 homologue, is also critical for keeping p53 in check until it is needed. Identification of new means of preventing the suppression of p53 by both Mdm2 and MdmX is an important component of the planned studies. We will study the regulation of p53 by Mdm2 and MdmX using biochemical and cellular approaches. It is planned to examine in detail several aspects of the RING domains of these two proteins. We will test a number of hypotheses including the proposition that the C-termini of Mdm2 and MdmX regulate the activity and specificity of the Mdm2 E3 ligase towards different target proteins. Another hypothesis is that there are critical differences in the modes by which Mdm2 and MdmX repress p53 transactivation which will be tested by extensive biochemical analyses. The third hypothesis, that stress signaling to p53 involves nucleolar disruption, is relevant to our finding that ribosomal protein RPS7 is both a regulator and substrate of Mdm2 and that RPS7 impacts the activity of Mdm2 after various forms of stress. We hope to eventually exploit findings from the proposed work for novel cancer therapies.
The p53 tumor suppressor is circumvented in the majority of human cancers. It is therefore essential to discover how to restore its anti-oncogenic activity. The goal of the planned research is to find ways to release p53 from it negative regulators Mdm2 and MdmX in tumors.
| 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 |
| Wu, Danyi; Prives, Carol (2018) Relevance of the p53-MDM2 axis to aging. Cell Death Differ 25:169-179 |
| 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 |
| Laptenko, Oleg; Shiff, Idit; Freed-Pastor, Will et al. (2015) The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain. Mol Cell 57:1034-1046 |
| 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 |
| Mansilla, Sabrina F; Soria, Gastón; Vallerga, María Belén et al. (2013) UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability. Nucleic Acids Res 41:6942-51 |
| 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 |
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