In response to signals of either endogenous or exogenous origins, mammalian cells implement changes in gene expression patterns that profoundly influence the global response of the cell. While the transcriptional events regulating changes in gene expression have been thoroughly studied, post-transcriptional processes, which are less well understood, are emerging as major gene 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 investigating the mechanisms that regulate the expression of proliferation-associated, cell cycle-regulatory, and stress-response gene products. To this end, we have focused specifically on sequence-specific RNA-binding proteins that regulate mRNA stability and translation. Our work on the RNA-binding protein HuR illustrates the approaches and scope of our studies. We have characterized the roles of HuR as a protein that can stabilize target mRNAs and sometimes promotes their translation. We have identified a large number of its target mRNAs, have elucidated a signature motif present in them, and have studied its nucleocytoplasmic shuttle, including an import factor responsible for its nuclear localization (importin-alpha 1), and a kinase (AMP-regulated protein kinase or AMPK) that regulates this transport. Our studies have demonstrated a clear role for HuR in regulating the expression of stress-response and proliferation genes in both primary, untransformed cells (fibroblasts, vascular smooth muscle cells, etc) and in cancer cells of various types. In the latter cell systems, HuR appears to increase the malignant phenotype by promoting proliferation, increasing angiogenesis, diminishing the cell?s ability to undergo senescence, and inhibiting apotosis.? ? We have now extended our efforts to other RNA-binding proteins that either promote mRNA decay (AUF1, TTP, BRF1, KSRP) or suppress translation (TIAR, TIA-1). For each of these post-transcriptional regulatory proteins, we are asking similar questions: what are their target mRNAs, what signaling events regulate their activity and/or localization, and what are their biological roles in systems of cancer and aging. Our long-term efforts are thus focused on investigating the ribonucleoprotein complexes that govern, on a post-transcriptional level, the expression of gene products which control cellular growth, responsiveness to stress stimuli, and senescence.
Showing the most recent 10 out of 80 publications
