Post-transcriptional control of Proliferation, Stress Response & Carcinogenesis

National Institute On Aging

Investigators

Linked publications & trials

Abstract

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. A major study from our lab identified a circular RNA ligand of AUF1, circPCNX), implicated in reducing cell proliferation by competing with p21 mRNA to increase p21 production (Tsitsipatis et al., Nucleic Acids Research, 2020). 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 in collaboration with other groups, including those led by Drs. J.-Y. Wang (Ting-Xi, et al., Cellular and Molecular Gastroenterology and Hepatology, 2020; Li et al., Molecular and Cellular Biology 2020; Xiao et al., Gastroenterology 2021). In collaboration with the Lal lab (NCI) we reported that a small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells (Li et al., eLife 2020). Collaborations with the Cucca lab resulted in reports on how the genetics of immune cells inform on autoimmunity and therapy (Orru et al., Nature Genetics, 2020) and on the influence of the BAFF-variant on the cellular and molecular responses to malaria antigens (Lodde, Frontiers in Immunology, 2020). Additional collaborations led to the identification of a circRNA that regulates p53 function (Chaudhary et al., Molecular and Cellular Biology, 2020), and the discovery that HuR modulates lipid homeostasis (Zhang et al., Nature Communications, 2020). Review articles from this period include a survey of circular RNAs in Blood Malignancies (Perez de Acha, Frontiers in Molecular Biosciences, 2020) and the influence of senescent cells in brain aging and Alzheimer's disease (Anerillas et al., GeroScience, 2020). We also reported a Practical Guide for circRNA analysis, offering steps, tips, and resources for rigorous analysis of circRNAs (Tsitsipatis et al., WIRES RNA, 2021).