In response to external and internal signals, mammalian cells elicit changes in gene expression patterns that profoundly influence the global cellular response. The transcriptional events that regulate gene expression changes have been thoroughly studied, but less-well understood post-transcriptional processes are emerging as major regulatory mechanisms. Post-transcriptional gene regulation includes pre-mRNA processing and maturation, mRNA transport, stability and translation, as well as protein processing, modification and degradation. We are keenly interested in the mechanisms that regulate the expression of proliferative, cell cycle-regulatory, and stress-response proteins. Over the past 10 years, this Project has examined mRNAs encoding various stress-response and proliferative proteins. During this funding period, we have focused our attention on mRNAs encoding heme oxygenase (HO)-1 and c-myc. We have reported that RBP associates with HO-1 mRNA and increases its stability in response to treatment with nitric oxide. We also reported that expression of the proto-oncogene and transcription factor c-myc is repressed by HuR through a mechanism that involves the recruitment of let-7 onto the c-Myc mRNA. Ongoing studies are examining the roles of RNA-binding proteins and microRNAs in the regulation of egr-1 expression in response to DNA-damaging agents, the expression of TOP2A, and the levels of HIF-1alpha after treatment with cobalt chloride and PX-478.
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