The decay of mRNA is central to the post-transcriptional regulation of gene expression. The expression of many clinically relevant genes, including cytokines, proto-oncogenes and growth factors, is regulated at the level of mRNA turnover through AU-rich elements (AREs) in their 3' untranslated regions. Therefore, studies of this process provide valuable insight into the deregulation of cellular mechanisms in some cancers and immune disorders. This proposal aims to use the yeast, Saccharomyces cerevisiae, as a model system to study the phenomenon of ARE-mediated mRNA decay. The enzymes and pathways of mRNA turnover are well characterized in this organism. Regulation of AREmediated mRNA decay in yeast occurs in response to at least two cellular stimuli and involves three identified factors; Publp, Cthlp and Cth2p. The goals of this proposal are to determine how (i) the ARE-binding complex regulates mRNA decay rates (ii) the ARE-binding complex is modulated in response to cellular stimuli and (iii) the complex of factors that assembles on the ARE is specified its sequence context. The first part of the proposal concentrates on characterization of the three ARE-binding proteins and the interactions among them and between them and the ARE. One important aspect focuses on dissecting the interaction between the Cth proteins and Pablp. In addition, experiments in this Aim will determine how these factors are post-translationally modified in response to cellular conditions.
Aim II of the proposal is to isolate ARE-binding complexes formed in vivo using both RNA tags and protein tags. Together the results of this part of the study will identify novel components of the ARE-binding complex and give us insight into how these complexes are altered in response to cellular conditions.
The final Aim of the proposal is to identify novel AU-rich elements in yeast through microarray analysis of mRNA decay rates in strains lacking the known ARE-binding factors and by analysis of candidate ARE-containing transcripts discovered by searching the Transterm database. The goal is to amass a set of AU-rich elements large enough to facilitate computer analysis of the sequences to identify commonalities between them that might specify the proteins they interact with and their regulation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Physiological Chemistry Study Section (PC)
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Rhoades, Marcus M
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University of Medicine & Dentistry of NJ
Schools of Medicine
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Vasudevan, Shobha; Garneau, Nicole; Tu Khounh, Danny et al. (2005) p38 mitogen-activated protein kinase/Hog1p regulates translation of the AU-rich-element-bearing MFA2 transcript. Mol Cell Biol 25:9753-63
Duttagupta, Radharani; Vasudevan, Shobha; Wilusz, Carol J et al. (2003) A yeast homologue of Hsp70, Ssa1p, regulates turnover of the MFA2 transcript through its AU-rich 3' untranslated region. Mol Cell Biol 23:2623-32