In response to external and internal signals, mammalian cells elicit post-transcriptional changes in gene expression patterns that govern the global cellular response. We are keenly interested in the mechanisms that regulate the expression of proliferative, cell cycle-regulatory, and stress-response proteins. Over the past 19 years, this Project has examined numerous RBPs, noncoding (nc)RNAs, and their influence on gene expression patterns. We have paid particular attention to their impact on the stress and proliferative response of cells, two processes that are severely impaired during aging. In the past funding period, we have continued to focus on RBPs implicated in the cellular response to mitogens and stresses, but have expanded substantially into ncRNAs that influence these responses. Since impaired adaptation to mitogens and cell injury underlie various cancer traits (cell proliferation and survival, angiogenesis, invasion, metastasis, and evasion of immune recognition), many studies in this project use cancer cells as the model system. Proliferation and stress response. We have continued to investigate the influence of RBPs and ncRNAs on the homeostasis of the intestinal epithelium, cancer cells, and immune cells. During this review period, many of these studies have been carried HuR in collaboration with other groups, including those led by Drs. Jian-Ying Wang (Ouyang et al., Biochemical Journal, 2015; Zou et al., American Journal of Physiology, 2015; Liu et al., Molecular Biology of the Cell, 2015; Chung et al., Molecular Medicine 2015; Zou et al., Molecular and Cellular Biology 2016; Xiao et al., Molecular Biology of the Cell 2016), Dr. Tom Misteli (Sharma et al., EMBO Reports, 2015), Craig Bassing (DeMicco et al., Journal of Immunology 2015), Alessia Pascale (Osera et al., RNA Biology 2015), Lucia Schuger (Yue et al., Journal of Biological Chemistry, 2015), Michele K Evans (Kim et al., Molecular and Cellular Biology 2015), Roopa Biswas (Tsuchiya et al., RNA Biology 2016), Placido Navas (Cascajo et al., RNA Biology 2015), and others. Our laboratory identified a long noncoding (lnc)RNA expressed ubiquitously in cancer cells (HeLa) that was capable of suppressing the function of an RNA-binding protein (HuR). This lncRNA (OIP5-AS1) was capable of binding large amounts of HuR and preventing the interaction of HuR with target mRNAs encoding proliferative proteins (Kim et al., Nucleic Acids Research 2016). Along these lines, we reviewed the post-translational regulation of HuR function in Grammatikakis et al., (WIRES RNA 2016). Tumorigenesis. We collaborated with Jonathan Brodys laboratory in the analysis of the role of RBP HuR in pancreatic tumorigenesis (Cozzitorto et al., Methods in Molecular Biology, 2015) and lung tumorigenesis with the group of Anupama Munshi (Mehta et al., Oncotarget 2016). The group led by Dr. Luiz Penalva collaborated with ours in studies of the RBP Musashi in glioblastoma (Uren et al., Molecular and Cellular Biology, 2015). Additional studies. Other articles during this review period characterized the ncRNAs involved in cancer, proliferation, stress-response, senescence, and other processes relevant to aging. We created a tool to investigate circular RNAs (Dudekula et al., RNA Biology 2016), published methodologies to detect circular RNAs (Panda et al., Methods in Molecular Biology 2016), and proposed future aspects of circular RNAs that must be investigated in order to elucidate their function (Panda et al., WIRES RNA 2016). Finally, we compiled the literature pertaining to lncRNAs and RBPs implicated in a range of cellular responses in Greco et al., (Journal of Molecular and Cellular Cardiology, 2015) and Yoon et al., (Methods in Molecular Biology, 2016).
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