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. With respect to mRNA stability, we are investigating the mechanisms that regulate the expression of various proliferation-associated, cell cycle regulatory, and stress-response gene products. We previously showed that the function of the RNA-binding protein HuR, which stabilizes target mRNAs, is strongly regulated by the AMP-activated kinase (AMPK). In follow-up studies, we recently found that AMPK promotes the nuclear localization of HuR by directly phosphorylating and indirectly acetylating importin a1. In separate investigations, 'en mass' analysis of HuR target transcripts using cDNA arrays recently revealed a ~20-b RNA motif present in HuR targets, which allows the successful prediction of novel HuR target transcripts. Other work has recently shown that multiple RNA-binding proteins influencing post-transcriptional fate in opposite directions (mRNA-stabilizing HuR and mRNA-destabilizing AUF1) were capable of binding target mRNAs simultaneously as well as competitively. With respect to translation, a series of systematic, cDNA-based studies have shed light on important links between enhanced mRNA stability and translational inhibition during the endoplasmic stress response.
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