Our goal is to elucidate the pathways and mechanisms involved in general and regulated mRNA stability, a process that plays an important role in controlling aspects of gene expression related to cell growth and differentiation. Our approach to this goal will largely center around a novel in vitro system we have developed and successfully exploited in the past that faithfully reproduces aspects of both general and regulated mRNA stability on exogenous RNA substrates. First, by strategic placement of structural blocks into RNA substrates, we will determine the in vivo pathways involved in the degradation of the body of the mRNA following deadenylation. Second, we will use an in vitro approach to determine how deadenylation of mRNA substrates is differentially regulated by distinct classes AU-rich elements. Third, we will determine how non-AU-rich elements, namely the pyrimidine-rich element of the important immune modulator CD154 and the U-rich element of the c-jun proto-oncogene, function to regulate mRNA stability. Finally, we have recently identified a complex of 3 proteins that assembles on the 3' UTR of an mRNA in a polyadenylation dependent manner. We will investigate the identity and functional significance of these proteins in a variety of post-transcriptional processes. These studies on the mechanisms and regulation of mRNA stability will have a profound impact on our appreciation of molecular mechanisms of cellular growth control, as well as providing insights into the molecular basis of disease (e.g. cancer) and possibly improved strategies for gene therapy.
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