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Characterization and regulation of the MED17-p53 binding interface.
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abstract
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The p53 protein is a transcription factor and tumor suppressor that is frequently mutated in human cancers. In response to a wide array of cellular stresses including DNA damage and overexpressed oncogenes, p53 binds DNA and regulates many target genes involved in DNA damage-repair, senescence, and apoptosis. Due to its potent anti-tumor activity, p53 remains an extremely viable biological target for cancer diagnostics and therapeutics. The human Mediator complex is a large transcriptional co-activator that promotes stimulus-specific gene expression through interactions with transcription factors and the general transcription machinery in a genome-wide fashion. It has been shown that the transactivation domain (TAD) of p53 interacts with Mediator through the MED17 subunit, and that this interaction is imperative for activated transcription. Despite the likely importance of this interaction for activation of p53 target genes, little high resolution and biochemical data of this complex is currently available. The overall goal is to characterize the p53 TAD-MED17 interaction and assess the effect that post-translational modifications (PTMs) have on the complex. Based on preliminary data, the current hypothesis is that a small domain of MED17 interacts with the p53 TAD, and that the affinity and specificity of this interaction coul be regulated through phosphorylation events in the p53 TAD. This proposal has two specific aims to accomplish this goal, (1) identify interacting residues within the MED17-p53 TAD binding interface and (2) identify p53 TAD post-translational regulatory sites in the MED17-p53 complex. The fulfillment of these aims will require the use of biochemical and biophysical assays such as GST binding assays, isothermal titration calorimetry (ITC), NMR, and X-ray crystallography. Additionally, functional and biological assays, including fully- reconstituted transcription assays, chromatin immunoprecipitation (ChIP), RT-qPCR, and microarray will be employed assess the biological relevance of this interaction and its manipulation. Elucidation of this interaction will provide a means to potentially regulate p53 activity in cells using either biological or chemical approaches.
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label
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Characterization and regulation of the MED17-p53 binding interface.
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