In response to external and internal signals, mammalian cells elicit post-transcriptional changes in gene expression patterns that govern the global cellular response. This regulation is carried out by controlling processes such as 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 15 years, this Project has examined numerous RBPs, noncoding (nc)RNAs, and their influence on gene expression patterns. We have paid particular attention to their influence on the stress and proliferative response of cells, two processes that are severely impaired during aging. In the past funding period, we have studied the influence of the RBP HuR on inflammation, proliferation, DNA damage, septic stress, and tumorigenesis (Fan et al, J. Immunol. 2011;Mazan-Mamczarz et al, Blood 2011;Masuda et al, EMBO J. 2011;Yu et al, Nuc. Acids Res. 2011;Srikantan et al, Mol. Cell. Biol. 2011;Tominaga et al, Mol. Cell. Biol. 2011;Vo et al, Mol. Cancer. Res. 2012). We also investigated the function of nucleolin and CUGBP1, two RBPs implicated in the stress response and proliferation (Abdelmohsen et al, Nuc. Acids Res. 2011;Cui et al, Mol. Biol. Cell 2012), as well as the function of actin-associated protein in transporting mRNAs in the cytoplasm (Chang et al, Proc. Natl. Acad. Sci. USA 2012). Other collaborative work has uncovered details of the activation of the insulin receptor (Wook et al, Science Signal. 2012) and gene expression patterns in liver cells exposed to stress agents (Song et al, J. Pharmacol. Exp. Ther. 2011). Also pertaining to this Project, we have contributed a number of reviews, editorials, and methods articles during this funding year. We reported a number of methods to identify RNA-protein interactions (Cozzitorto et al, Pancreatic Cancer, Methods and Protocols 2012;Khan et al, Molecular Biology Techniques for the Surgeon, 2012;Yoon et al, Methods, 2012;Fan et al, Methods Mol. Biol. 2011) and previewed an article that discussed important methodological issues (Srikantan and Gorospe, Mol. Cell 2011). We reviewed the topic of mRNA decay during the cellular stress response (Srikantan and Gorospe, Regulation of Organelle and Cell Compartment Signaling, 2011), and surgical stress in the elderly population (Kowdley et al., The Scientific World Journal, 2012). More basic aspects of the stress response, including stem cell glycobiology and the cellular response to hypoxic stress, were also reviewed (Gorospe et al, Front. Mol. Neurosci. 2011;Srikantan and Gorospe, Aging 2012), as were aspects of the interplay between HuR and microRNAs (Srikantan et al, Curr. Prot. Pept. Sci. 2012).
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