Research Projects
In our lab, we study the mechanisms that regulate gene expression at the posttranscriptional level. Currently, projects are available in three areas.
Studies on the Regulation of mRNA Stability
Many mRNAs contain cis-acting elements that direct their rapid turnover. The first cis-acting sequence to be described was the U-rich or Shaw-Kamen element. In unstimulated cells, mRNAs that contain U-rich elements rapidly disappear. Upon appropriate stimulation, a specific mRNA/protein complex is formed, decay is blocked, and a rapid rise in the steady state level of the mRNA ensues. We have shown that a family of mRNA binding proteins stabilizes such mRNAs. We first discovered these proteins as human tumor antigens that elicit autoimmune neurological disorders. These RNA binding proteins are called the Elav-like proteins because of their homology to Elav, a Drosophila protein that regulates neuronal differentiation. The way in which cellular signals activate the binding of the Elav-like proteins to mRNA is one focus of our future efforts. To more clearly understand how the Elav-like proteins work it is critical to understand the specific mRNA decay mechanism that is directed by the Shaw-Kamen element. Therefore, we are also studing the mechanism of action of proteins such as TTP and BRF which specifically direct the degradation of U-rich element containing mRNAs.
The Mechanism of Action of miRNAs
Micro RNAs, or miRNAs are, small single stranded non-coding RNAs that silence gene expression by directly annealing to a complementary target mRNA. Recently, in the last year, we have reconstituted the action of miRNAs in a cell-free system using extracts from human cells. We have found that the let-7 miRNA directs the cleavage of its lin-41 mRNA target. Future studies will focus on how miRNAs catalyze the cleavage of mRNA and the identification of the protein components of the miRNA/mRNA complex.
A New mRNA Splicing Pathway
Recently, it has become clear that mRNA may be spliced a by non-spliceosommal mechanism. In mammals and yeast, the unfolded protein response directs the alternative splicing of mRNA. In this pathway, the mRNA is cleaved by a specific endonuclease (the IREp protein in yeast) and is believed to be spliced by a putative RNA ligase that requires 2'3'cylic phosphate termini. Our aim is to identify this novel RNA ligase in mammalian cells.
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