Posttranscriptional Regulation Of Genes Controling Cell Growth And Proliferation

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Abstract

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. [unreadable] [unreadable] 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 previously characterized the roles of HuR as a protein that can stabilize target mRNAs and sometimes promote 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 (importin-alpha 1) and kinase (AMPK) responsible for its nuclear localization. More recently, we have identified CHK2 (checkpoint 2) as a kinase that influences HuR binding to target mRNAs, including the sirtuin-1 (Sirt1) mRNA. 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 cells ability to undergo senescence, and inhibiting apotosis.[unreadable] [unreadable] We have also extended our efforts to other RNA-binding proteins that either promote mRNA decay (AUF1, TTP, BRF1, KSRP) or suppress translation (TIAR, TIA-1). Over the past year, we have elucidated a signature motif for TIAR which was unexpectedly C-rich and triggered the dissociation of target mRNAs from TIAR in response to stress. We have also reported that many of these regulatory RBPs can influence the expression of other RBPs through binding to cognate mRNAs.