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Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (SDM) of arginine, a posttranslational modification involved in oncogenesis and embryonic development. However, the role and mechanisms by which PRMT5 modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMT5 promoted SREBP1 SDM and the induction of cholesterol biosynthetic pathway enzymes that produce retinoid-related orphan receptor (ROR) agonists that activate [ROR[gamma]t. Specific loss of PRMT5 in the [CD4.sup.+] Th cell compartment suppressed Th17 differentiation and protected mice from developing experimental autoimmune encephalomyelitis (EAE). We also found that PRMT5 controlled thymic and peripheral homeostasis in the [CD4.sup.+] Th cell life cycle and invariant NK (iNK) T cell development and [CD8.sup.+] T cell maintenance. This work demonstrates that PRMT5 expression in recently activated T cells is necessary for the cholesterol biosynthesis metabolic gene expression program that generates [ROR[gamma]t agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases., Introduction Arginine methylation is a posttranslational modification of histones and other proteins that regulates important physiological processes, including stem cell biology, differentiation, and development. Conversely, arginine methylation dysregulation occurs in [...]

P-loop NTPases comprise one of the major superfamilies of nucleotide binding proteins, which mediate a variety of cellular processes, such as mRNA translation, signal transduction, cell motility, and growth regulation. In this review, we discuss the structure and function of two members of the ancient Obg-related family of P-loop GTPases: human Obg-like ATPase 1 (hOLA1), and its bacterial/plant homolog, YchF. After a brief discussion of nucleotide binding proteins in general and the classification of the Obg-related family in particular, we discuss the sequence and structural features of YchF and hOLA1. We then explore the various functional roles of hOLA1 in mammalian cells during stress response and cancer progression, and of YchF in bacterial cells. Finally, we directly compare and contrast the structure and function of hOLA1 with YchF before summarizing the future perspectives of hOLA1 research. This review is timely, given the variety of recent studies aimed at understanding the roles of hOLA1 and YchF in such critical processes as cellular-stress response, oncogenesis, and protein synthesis. Key words: hOLA1, YchF, cellular stress, cancer progression, structure--function. Les NTPases a boucle P constituent une des principales superfamilles de proteines de liaison des nucleotides qui interviennent dans une variete de processus cellulaires tels que la traduction de l'ARNm, la transduction de signaux, la motilite cellulaire et la regulation de la croissance. Dans cette synthese, les auteurs discutent de la structure et de la fonction de deux membresdelafamille anciennedeGTPasesabouclePrelieesaObg:l'ATPasedetype obg humaine hOLA1etson homologue chez les bacteries et les vegetaux, YchF. Apres une breve presentation des proteines de liaison des nucleotides en general et de la classification de la famille reliee a Obg en particulier, les auteurs discutent des caracteristiques de sequences et structurales de YchF et de hOLA1. Ils explorent ensuite les differents roles fonctionnels de hOLA1 dans les cellules de mammiferes durant la reponse au stress et la progression du cancer, ainsi que ceux de YchF dans les cellules bacteriennes. Finalement, ils comparent et exposent directement les differences entre la structure et la fonction de hOLA1 et celles de YchF, avant de resumer les perspectives de larecherche sur hOLA1. Cette synthese tombe a point nomme, compte tenu dela variete d'etudes recentes visant a comprendre les roles de hOLA1 et de YchF dans des processus importants comme la reponse cellulaire au stress, l'oncogenese et la synthese des proteines. [Traduit par la Redaction] Mots-cles : hOLA1, YchF, stress cellulaire, progression du cancer, structure--fonction., Introduction Nucleotide binding proteins Nucleotide binding proteins have vital roles in cellular processes including mRNA translation, signal transduction, cell motility, cell division, cell growth, chromatin remodeling, and cytoskeleton organization (Milligan [...]

The softshell Mya arenaria is an ecologically and commercially important bivalve mollusc that develops a fatal cancer known as disseminated neoplasia or hemocyte leukemia. This cancer, like many human cancers, involves the master control gene of apoptosis, p53. This gene is also known to interact with retrotransposons, and a growing body of evidence suggests that p53 actually controls retrotransposon expression and subsequently oncogenesis. The recent description of a retrotransposon (i.e.. Steamer) in adult M. arenaria and its potential involvement in the oncogenesis of hemocyte leukemia has been suggested. Juvenile clams, previously shown not to develop hemocyte leukemia, were exposed to climate-related changes in seawater temperature and pH predicted for the year 2100. All juvenile softshells do express the retrotransposon Steamer. When juvenile clams are exposed to predicted climate-related changes in temperature and pH in the Gulf of Maine, it significantly induces Steamer expression, specifically in treatments where clams were exposed to low pH. For juvenile individuals of M. arenaria and potentially other bivalves. Steamer may be a candidate biomarker for exposure to ocean acidification conditions. KEY WORDS: Steamer, climate change, ocean acidification, Mya arenaria, softshell, clam, cancer, apoptosis. retrotransposon, INTRODUCTION The softshell Mya arenaria (Linnaeus, 1758) is found worldwide in marine soft-bottom ecosystems where it is ecologically important in the coupling of water column productivity to benthic consumers and [...]

microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications., Introduction miRNAs are small endogenous non-protein-coding RNAs that posttranscriptionally regulate the expression of multiple target genes in different cell types. In this manner, miRNAs control many physiological cellular processes, as [...]

Patients with type 1 or type 2 diabetes have an insufficiency in their functional [beta] cell mass. To advance diabetes treatment and to work toward a cure, a better understanding of how to protect the pancreatic [beta] cells against autoimmune or metabolic assaults (e.g., obesity, gestation) will be required. Over the past decades, [beta] cell protection has been extensively investigated in rodents both in vivo and in vitro using isolated islets or rodent [beta] cell lines. Transferring these rodent data to humans has long been challenging, at least partly for technical reasons: primary human islet preparations were scarce and functional human [beta] cell lines were lacking. In 2011, we described a robust protocol of targeted oncogenesis in human fetal pancreas and produced the first functional human [beta] cell line, and in subsequent years additional lines with specific traits. These cell lines are currently used by more than 150 academic and industrial laboratories worldwide. In this Review, we first explain how we developed the human [beta] cell lines and why we think we succeeded where others, despite major efforts, did not. Next, we discuss the use of such functional human [beta] cell lines and share some perspectives on their use to advance diabetes research., Introduction The only hormone that can decrease circulating glucose levels is insulin. Insulin is produced in [beta] cells, and its secretion into the bloodstream is tightly regulated to control glucose [...]

Transcription factor fusion genes create oncoproteins that drive oncogenesis and represent challenging therapeutic targets. Understanding the molecular targets by which such fusion oncoproteins promote malignancy offers an approach to develop rational treatment strategies to improve clinical outcomes. Capicua-double homeobox 4 (CIC-DUX4) is a transcription factor fusion oncoprotein that defines certain undifferentiated round cell sarcomas with high metastatic propensity and poor clinical outcomes. The molecular targets regulated by the CIC-DUX4 oncoprotein that promote this aggressive malignancy remain largely unknown. We demonstrated that increased expression of ETS variant 4 (ETV4) and cyclin E1 (CCNE1) occurs via neomorphic, direct effects of CIC-DUX4 and drives tumor metastasis and survival, respectively. We uncovered a molecular dependence on the CCNE-CDK2 cell cycle complex that renders CIC-DUX4-expressing tumors sensitive to inhibition of the CCNE-CDK2 complex, suggesting a therapeutic strategy for CIC-DUX4-expressing tumors. Our findings highlight a paradigm of functional diversification of transcriptional repertoires controlled by a genetically aberrant transcriptional regulator, with therapeutic implications., Introduction The biological regulation of transcription factors and repressor proteins is an essential mechanism for maintaining cellular homeostasis, and is often dysregulated in human cancer (1). Indeed, chromosomal rearrangements involving [...]

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms.sup.1 by synchronization to environmental cues and is involved in diverse physiological processes.sup.2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function.sup.3. Melatonin is formed in the pineal gland in a light-regulated manner.sup.4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness.sup.5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT.sub.1) and type 1B (MT.sub.2).sup.3,6. Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden.sup.7. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids.sup.8,9, and is one of the most popular supplements in the United States.sup.10. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT.sub.1 in complex with four agonists: the insomnia drug ramelteon.sup.11, two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine.sup.12,13. The structure of MT.sub.2 is described in an accompanying paper.sup.14. Although the MT.sub.1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT.sub.1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT.sub.1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors. The MT.sub.1 melatonin receptor differs markedly from 5-HT receptors and shows atypical ligand entry; its structure with various ligands sheds light on receptor specificity., Author(s): Benjamin Stauch [sup.1] [sup.2] , Linda C. Johansson [sup.1] [sup.2] , John D. McCorvy [sup.4] [sup.15] , Nilkanth Patel [sup.1] [sup.3] , Gye Won Han [sup.1] [sup.2] , Xi-Ping [...]

The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing or remaining static. The cellular basis of this clinical observation is unknown. Here, we profile the genomic, transcriptomic, and epigenomic landscape of CIS in a unique patient cohort with longitudinally monitored pre-invasive disease. Predictive modeling identifies which lesions will progress with remarkable accuracy. We identify progression-specific methylation changes on a background of widespread heterogeneity, alongside a strong chromosomal instability signature. We observed mutations and copy number changes characteristic of cancer and chart their emergence, offering a window into early carcinogenesis. We anticipate that this new understanding of cancer precursor biology will improve early detection, reduce overtreatment, and foster preventative therapies targeting early clonal events in lung cancer. A multi-omics survey of progressive compared to regressive carcinoma in situ lesions provides a molecular map of early lung cancer development., Author(s): Vitor H. Teixeira [sup.1] , Christodoulos P. Pipinikas [sup.1] [sup.2] , Adam Pennycuick [sup.1] , Henry Lee-Six [sup.3] , Deepak Chandrasekharan [sup.1] , Jennifer Beane [sup.4] , Tiffany J. [...]

Neutrophils are early wound healing and inflammation regulators that, due to functional plasticity, can adopt either pro- or antitumor functions. Until recently, beclin-1 was a protein known mainly for its role as a critical regulator of autophagy. In this issue of the JCI, Tan et al. describe the effects of the beclin-1 conditional myeloid cell-specific deletion in mice, in which immunostimulation resulted in hypersensitive neutrophils. The chronic proinflammatory effect of these neutrophils triggered spontaneous B cell malignancies to develop. Such tumorigenic effects were mediated primarily by IL-21 and CD40 signaling, leading to the upregulation of tolerogenic molecules, such as IL-10 and PD-L1. The authors went on to examine samples derived from patient lymphoid malignancies and showed that beclin-1 expression in neutrophils positively correlated with pre-B cell leukemia/lymphoma. Overall, the study provides an elegant model for neutrophil-driven carcinogenesis and identifies potential targets for immunotherapy of B cell malignancies., Neutrophils in the tumor microenvironment Tumor progression is defined by both cancer cell-intrinsic effects, related to genetic and epigenetic phenomena, and extrinsic influences of various nonmalignant stromal cells (1). In [...]