Department of Biochemistry

Understanding how mRNA levels are controlled in eukaryotes requires dissection of the intricate pathway responsible for the synthesis and processing of mRNA. Previously, we obtained evidence for a general eukaryotic transcription regulatory process that controls the number of polymerase molecules that are able to produce full-length mRNAs. We discovered P-TEFb, a cyclin dependent kinase that plays a key role in this elongation control process. The kinase activity of P-TEFb is generally required for eukaryotic gene expression and recent results indicate that cells carefully regulate P-TEFb through an unusual association with a small RNA called 7SK. We are currently engaged in projects to uncover the mechanism of P-TEFb function and how it is regulated. The AIDS virus, HIV, encodes a protein, Tat, that enables the virus to take over the control of P-TEFb. We are studying Tat-transactivation and are examining the mechanism of action of drugs that target this critical step in the HIV life cycle. One such drug, flavopiridol, is in clinical trials as an anti-cancer therapy. We have shown that flavopiridol targets the kinase activity of P-TEFb and this can block the growth of cancer cells and at lower concentrations block HIV replication.