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 16 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 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), most studies in this project use cancer cells as the model system. Proliferation and stress response. We have continued to investigate the influence of HuR on cell division. During this review period, we studied several post-transcriptional and post-translational mechanisms controlling HuR expression and function. We have also continued to study the role of HuR on the cellular response to damaging agents. Exposure to the oxidant hydrogen peroxide, to nitric oxide and to hypoxia regulated HuR activity. In an animal model of surgical stress, HuR competed with the RBP CUGBP1 (CUG-binding protein 1) to drive expression of occludin, as documented in collaborative studies (Yu et al., Mol Biol Cell, 2013). Tumorigenesis. The ability of HuR to promote tumorigenic traits continued to be revealed during this review period. Collaborative studies lent support to the notion that HuR competes with miR-195 to modulate Stim1 production and thereby regulate cell migration Zhuang et al., Nuc. Acids Res 2013. Numerous ncRNAs that suppress tumorigenesis were also studied during this funding period. Tumor-suppressor microRNAs, including several that trigger senescence (e.g., let-7, miR-34, and miR-519), were recently reviewed and discussed (Grammatikakis et al., Intl J Med Sci, 2013). The expression and stability of the long intergenic noncoding (linc)RNA-p21 were negatively regulated by HuR;since lincRNA-p21 repressed the translation of the anti-apoptotic proteins JunB and -catenin, HuR further promoted a pro-survival phenotype through its influence on lincRNA-p21 (Yoon et al., Mol Cell, 2012). This work inspired a review that summarized the post-transcriptional regulation of lncRNAs thus far (Yoon et al., J Mol Biol, 2012). Additional work was done during this review period in order to fully characterize the RBPs and ncRNAs involved in cancer, proliferation, stress-response, senescence, and other processes relevant to aging. Loss of the RBP AUF1 in cells accelerated senescence, while AUF1-null mice showed premature aging. However, the systematic collection of AUF1-associated mRNAs is not fully known;moreover, since AUF1 represses Dicer expression, AUF1 appears to affect broadly the profiles of expressed microRNAs (Abdelmohsen et al., Nuc Acids Res 2012). Nucleolin also has a wide spectrum of functions, including carcinogenesis (Abdelmohsen and Gorospe, RNA Biol, 2012), but the subset of bound mRNAs was only recently identified (Abdelmohsen et al., Nuc Acids Res, 2013). Given that nucleolin expression is regulated through competition between HuR and miR-494, we recently reviewed the interplay between HuR and microRNAs (Srikantan et al., Curr Prot Pept Sci 2012). Finally, we have reported several methodologies, among which are a technique to screen for factors associated in an RNA of interest that is tagged with MS2 hairpins (Yoon et al., Methods, 2012) and a method to measure the levels of functional microRNAs (Guo et al., PLoS ONE, 2013).
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