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 linear long noncoding RNAs (lnc)RNAs and circular (circRNAs) 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 (Zou et al., Molecular and Cellular Biology 2016; Xiao et al., Molecular Biology of the Cell 2016; Liu et al., Molecular and Cellular Biology, 2017; Zhang et al., Molecular and Cellular Biology, in press 2017), Roopa Biswas (Tsuchiya et al., RNA Biology 2016), Jae-Seon Lee (Lee et al., Nucleic Acids Res 2017), Prasanth (Anantharaman et al., Nucleic Acids Res 2017), Alessandro Provenzani (Lal et al., Nucleic Acids Research 2017), Jackie Wilce (Nucleic Acids Res 2017) and others. In this funding period, we collaborated on studies that identified lncRNA MIR100 as implicated in cell division (Sun et al., Nucleic Acids Research 2018) and reported that stress-regulated RNA editing enzymes ADAR1 and ADAR2 influence the expression of numerous substrate RNAs (Anantharaman et al., FEBS Letters, 2018). TUMORIGENESIS. We recently collaborated with the group of Anupama Munshi to study HuR function in breast cancer (Mehta et al., Oncotarget 2016) and discussed the impact of RBP UNR in melanoma (Weeraratna and Gorospe, Cancer Cell 2017). During this review period, we have reviewed the different levels of regulation of p53 expression and function by the RBP HuR (Yang and Gorospe, Noncoding RNA Investigation 2018), collaborated in the identification of an inhibitor of HuR function (Lal et al., Nucleic Acids Res 2018) and previewed the role of cytoplasmic lncRNA CASC9 in hepatocellular carcinoma survival (Noh et al., 2018). STUDIES FOCUSED ON EPITHELIAL INTEGRITY. The integrity of the intestinal epithelium, which declines with age, continues to be an area of intense study in collaboration with the Wang laboratory at the University of Maryland at Baltimore. In this funding period, our groups reported that 4 coordinates small intestinal epithelium homeostasis by regulating the stability of HuR (Chung et al., Molecular and Cellular Biology, 2018), that the lncRNA uc.173 regulates the strength of the intestinal barrier (Wang et al., Molecular and Cellular Biology, 2018), miR-195 and RBP CUGBP1 jointly repress IGF2R translation in the intestinal epithelium (Zhang et al, Molecular and Cellular Biology, 2017), and that lncRNA uc.173 enhances intestinal mucosal renewal by suppressing miR-195 (Xiao et al., Gastroenterology, 2017). 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; Panda et al., Nucleic Acids Research 2017), and proposed future aspects of circular RNAs that must be investigated in order to elucidate their function (Panda et al., WIRES RNA 2016). The topic of extracellular vesicles is an area of expansion in the laboratory; we reviewed progress in this field (Kim et al., WIRES RNA 2017). Over the past 12 months, we have reported methods articles on the design of divergent primers to detect circular RNAs by RT-PCR analysis (Panda et al., Bio-Protocols, 2018), have published a novel method to enrich circular RNAs among complex RNA pools (Panda et al., Nucleic Acids Research, 2017), and have identified en masse senescence-associated circular RNAs (SAC-RNAs) (Panda et al., Nucleic Acids Research, 2017).
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