Eukaryotic Gene Expression
We have a broad interest in the biochemical mechanisms that regulate gene expression in
eukaryotes. We pursue this
interest using a variety of experimental systems and approaches that involve molecular biological, biochemical and
genetic methodology. Thus, investigators in this laboratory are exposed to diverse scientific questions, systems and
experimental approaches, facilitating their training as generalists.
Much of gene regulation occurs at the transcriptional level. A central question in the field is how do
promoter-specific activator proteins (activators) communicate with the general transcription machinery to stimulate
transcription? We have developed assays that monitor the assembly of general transcription factors onto the DNA
template in response to an activator. The results of these studies have suggested models for how transcription
activation occurs. Predictions of these models are then tested using in vivo systems including mammalian cells and
yeast.
A second, broad question is how are transcriptional activators themselves regulated? To address this issue, we
largely turn to animal viruses, which have provided important models for studying gene expression in higher
eukaryotes. Many of these viruses encode regulatory proteins that redirect cellular transcription components to
express viral genes. We study how such transcriptional regulators as the adenovirus E1a protein, the Tax protein of
human T-cell leukemia virus (HTLV), the pX protein of Hepatitis B Virus (HBV), and the Tat protein of Human
Immunodeficiency Virus (HIV) work.
In higher eukaryotes gene expression is also regulated at the post-transcriptional level. For example, by alternative
processing of an mRNA precursor (pre-mRNA) multiple polypeptides can be generated from a single gene. Splicing
occurs in a large multi-subunit complex, the spliceosome, the formation of which is dependent upon multiple proteins
and small nuclear ribonucleoprotein proteins (snRNPs). We are particularly interested in splicing factors that act
early during spliceosome assembly; these factors play a critical role in defining splice sites and are targets for splicing
regulators. Through these studies we seek to understand how the specificity and accuracy of splicing is achieved, the
basis of catalysis, and the mechanisms involved in alternative splicing. Another RNA processing event we are
studying is the export of the fully processed mRNA from the nucleus to the cytoplasm. Again, viral regulatory
proteins, such as the HIV Rev protein, provide attractive model systems.
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