Adenosine (Ado) is an important signaling molecule involved in stress responses. Studies in mammalian models have shown that Ado regulates signaling mechanisms involved in "danger-sensing" and tissue-protection. Yet, little is known about the role of Ado signaling in Drosophila. In the present study, we observed lower extracellular Ado concentration and suppressed expression of Ado transporters in flies expressing mutant huntingtin protein (mHTT). We altered Ado signaling using genetic tools and found that the overexpression of Ado metabolic enzymes, as well as the suppression of Ado receptor (AdoR) and transporters (ENTs), were able to minimize mHTT-induced mortality. We also identified the downstream targets of the AdoR pathway, the modifier of mdg4 (Mod(mdg4)) and heat-shock protein 70 (Hsp70), which modulated the formation of mHTT aggregates. Finally, we showed that a decrease in Ado signaling affects other Drosophila stress reactions, including paraquat and heat-shock treatments. Our study provides important insights into how Ado regulates stress responses in Drosophila.

• Keywords
• cytotoxicity, equilibrative nucleoside transporter, heat-shock protein 70, modifier of mdg4, mutant huntingtin, neurodegeneration,
• Publication type
• Journal Article MeSH

BACKGROUND: Epigenetic modifications including DNA methylation and post-translational modifications of histones are known to regulate gene expression. Antagonistic activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) mediate transcriptional reprogramming during insect development as shown in Drosophila melanogaster and other insects. Juvenile hormones (JH) play vital roles in the regulation of growth, development, metamorphosis, reproduction and other physiological processes. However, our current understanding of epigenetic regulation of JH action is still limited. Hence, we studied the role of CREB binding protein (CBP, contains HAT domain) and Trichostatin A (TSA, HDAC inhibitor) on JH action. RESULTS: Exposure of Tribolium castaneum cells (TcA cells) to JH or TSA caused an increase in expression of Kr-h1 (a known JH-response gene) and 31 or 698 other genes respectively. Knockdown of the gene coding for CBP caused a decrease in the expression of 456 genes including Kr-h1. Interestingly, the expression of several genes coding for transcription factors, nuclear receptors, P450 and fatty acid synthase family members that are known to mediate JH action were affected by CBP knockdown or TSA treatment. CONCLUSIONS: These data suggest that acetylation and deacetylation mediated by HATs and HDACs play an important role in JH action.

• Keywords
• FOXO Tribolium and TcA cells, HAT, HDAC, Kr-h1,
• MeSH
• Acetylation MeSH
• RNA, Double-Stranded metabolism   MeSH
• Epigenesis, Genetic drug effects   MeSH
• Insect Proteins antagonists & inhibitors   genetics   metabolism   MeSH
• Hydroxamic Acids pharmacology   MeSH
• CREB-Binding Protein antagonists & inhibitors   genetics   metabolism   MeSH
• RNA Interference MeSH
• Tribolium drug effects   growth & development   metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• RNA, Double-Stranded MeSH
• Insect Proteins MeSH
• Hydroxamic Acids MeSH
• CREB-Binding Protein MeSH
• trichostatin A MeSH Browser

Drosophila imaginal disc growth factor 2 (IDGF2) is a member of chitinase-like protein family (CLPs) able to induce the proliferation of imaginal disc cells in vitro. In this study we characterized physiological concentrations and expression of IDGF2 in vivo as well as its impact on the viability and transcriptional profile of Drosophila cells in vitro. We show that IDGF2 is independent of insulin and protects cells from death caused by serum deprivation, toxicity of xenobiotics or high concentrations of extracellular adenosine (Ado) and deoxyadenosine (dAdo). Transcriptional profiling suggested that such cytoprotection is connected with the induction of genes involved in energy metabolism, detoxification and innate immunity. We also show that IDGF2 is an abundant haemolymph component, which is further induced by injury in larval stages. The highest IDGF2 accumulation was found at garland and pericardial nephrocytes supporting its role in organismal defence and detoxification. Our findings provide evidence that IDGF2 is an important trophic factor promoting cellular and organismal survival.

• MeSH
• Drosophila immunology   metabolism   MeSH
• Energy Metabolism * MeSH
• Glycoproteins metabolism   MeSH
• Hemolymph chemistry   MeSH
• Cells, Cultured MeSH
• Inactivation, Metabolic * MeSH
• Immunity, Innate * MeSH
• Drosophila Proteins metabolism   MeSH
• Gene Expression Profiling MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glycoproteins MeSH
• Idgf2 protein, Drosophila MeSH Browser
• Drosophila Proteins MeSH

Adenosine (Ado) is a ubiquitous metabolite that plays a prominent role as a paracrine homeostatic signal of metabolic imbalance within tissues. It quickly responds to various stress stimuli by adjusting energy metabolism and influencing cell growth and survival. Ado is also released by dead or dying cells and is present at significant concentrations in solid tumors. Ado signaling is mediated by Ado receptors (AdoR) and proteins modulating its concentration, including nucleoside transporters and Ado deaminases. We examined the impact of genetic manipulations of three Drosophila genes involved in Ado signaling on the incidence of somatic mosaic clones formed by the loss of heterozygosity (LOH) of tumor suppressor and marker genes. We show here that genetic manipulations with the AdoR, equilibrative nucleoside transporter 2 (Ent2), and Ado deaminase growth factor-A (Adgf-A) cause dramatic changes in the frequency of hyperplastic outgrowth clones formed by LOH of the warts (wts) tumor suppressor, while they have almost no effect on control yellow (y) clones. In addition, the effect of AdoR is dose-sensitive and its overexpression leads to the increase in wts hyperplastic epithelial outgrowth rates. Consistently, the frequency of mosaic hyperplastic outgrowth clones generated by the LOH of another tumor suppressor, discs overgrown (dco), belonging to the wts signaling pathway is also dependent on AdoR. Our results provide interesting insight into the maintenance of tissue homeostasis at a cellular level.

• MeSH
• Drosophila melanogaster MeSH
• Membrane Transport Proteins genetics   MeSH
• Mutation * MeSH
• Drosophila Proteins genetics   MeSH
• Receptors, Purinergic P1 genetics   MeSH
• Signal Transduction genetics   MeSH
• Loss of Heterozygosity MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• adenosine deaminase-related growth factor, Drosophila MeSH Browser
• ENT2 protein, Drosophila MeSH Browser
• Membrane Transport Proteins MeSH
• Drosophila Proteins MeSH
• Receptors, Purinergic P1 MeSH