In mammals, the expression of proteins regulating cell proliferation and differentiation is tightly controlled, since disregulated production of these factors contributes to oncogenesis and other serious clinical syndromes. For mRNAs encoding oncoproteins and cytokines, this regulation includes rapid cytoplasmic mRNA degradation directed by AU-rich elements (AREs), a diverse but evolutionarily conserved family of sequences encoded within the 3' untranslated regions of these transcripts. Our long-term objectives are to determine how the size and sequence diversity of AREs contributes to post-transcriptional regulation at the gene-specific level, and how gene-specific characteristics of AREs might ultimately be exploited as targets for novel therapies to treat some cancers and chronic inflammatory diseases. These goals will be pursued by quantitatively examining the biochemical and cell biological consequences of interactions between different AREs and a number of cytoplasmic ARE-binding proteins, based on the hypothesis that each ARE preferentially associates with a subset of ARE-binding proteins where: (i) binding preference is dictated by primary and/or higher-order RNA structures within the ARE, and (ii) preferential factor occupancy on the ARE directs the mRNA to one of a number of possible catabolic or protected fates. To test this hypothesis, the structural and functional consequences of interactions between model AREs and a panel of ARE-binding proteins will be assessed through three Specific Aims. First, the RNA sequence requirements and structural consequences of recombinant trans-factor binding to AREs from selected cellular mRNAs will be identified in vitro, largely by coupling RNA mutagenesis with quantitative, fluorescence-based assays of RNA-protein equilibria. Second, higher-order RNA structures involving AREs from different cellular mRNAs will be identified in vitro by nuclease footprinting and fluorescence resonance energy transfer, and their role in modulating trans-factor binding quantitatively assessed. Finally, the ability of selected trans-acting factors to modulate the turnover rates of reporter mRNAs will be tested in a transfected cell system by ectopic overexpression and/or RNA interference-mediated depletion of each factor. Together, these experiments will define gene- or gene family-specific features of AREs that dictate the cytoplasmic fate(s) of mRNAs encoding them, and will identify which specific trans-acting factor(s) mediate these fates for individual mRNAs.
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| Hwang, Bor-Jang; Jin, Jin; Gunther, Randall et al. (2015) Association of the Rad9-Rad1-Hus1 checkpoint clamp with MYH DNA glycosylase and DNA. DNA Repair (Amst) 31:80-90 |
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| Xu, Li; Ning, Huan; Gu, Ling et al. (2015) Tristetraprolin induces cell cycle arrest in breast tumor cells through targeting AP-1/c-Jun and NF-?B pathway. Oncotarget 6:41679-91 |
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| Wells, Melissa L; Washington, Onica L; Hicks, Stephanie N et al. (2015) Post-transcriptional regulation of transcript abundance by a conserved member of the tristetraprolin family in Candida albicans. Mol Microbiol 95:1036-53 |
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