The Hypoxia-Inducible Factor-1α in Angiogenesis and Cancer: Insights from the Drosophila Model

The hypoxia-inducible factor-1α (HIF-1α) is an evolutionarily conserved transcription factor with prominent roles in the hypoxic response, cell survival, angiogenesis and cancer. HIF-1α functions as a sensor of molecular oxygen: in the presence of oxygen, it is degraded by the proteasome, whereas in reduced oxygen tensions, it heterodimerizes with the constitutively expressed HIF-1b subunit forming the functional HIF1 transcription factor, which enters the nucleus to control expression of hypoxia-inducible genes. Since HIF-1α has been found upregulated in several cancers, it has attracted a lot of clinical interest, because it represents an interesting candidate for pharmacological chemotherapy interventions. In this chapter, we discuss our current knowledge on the HIF1 transcription factors and their major roles in development, physiology, angiogenesis and cancer using examples of recent studies in the model organism Drosophila melanogaster. Given the striking functional conservation between the mammalian and fruit fly HIF-1α, we expect that future studies in the Drosophila model will not only expand our knowledge on the basic HIF1 biology, but they will also pinpoint conserved molecular regulators of HIF1 that might lead to the discovery of novel cancer therapeutics

Homeostasis in Infected Epithelia: Stem Cells Take the Lead

To maintain tissue homeostasis and avoid disease, epithelial cells damaged by pathogens need to be readily replenished, and this is mainly achieved by the activation of stem cells. In this Short Review, we discuss recent developments in the exciting field of host epithelia-pathogen interaction in Drosophila as well as in mammals

Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis

Work in the A.K. laboratory was co-funded by the European Regional Development Fund and the Republic of Cyprus through the Research & Innovation Foundation (Projects: EXCELLENCE/0918/0081, EXCELLENCE/0918/0105 and EXCELLENCE/1216/0215) and was also supported by a Marie Skłodowska-Curie individual fellowship grant (no. 890750) to E.C. JLG’s laboratory is supported by the Wellcome Trust (Equipment grant 093,148/Z/10/Z)), the Medical Research Council (G0801841 & UD99999906), and UK Dementia Research Institute. The K.S. laboratory is co-funded by the European Regional Development Fund and the Republic of Cyprus through the Research & Innovation Foundation (Projects: OPPORTUNITY/0916/ERC-StG/003,INFRASTRUCTURES/1216/0034POST-DOC/0916/0111, INTERNATIONAL/OTHER/0118/0018).Peer reviewe

Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.

BACKGROUND: Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown. Here, we tested this notion by investigating the function of N-alpha-acetyltransferase 40 (NAA40), the enzyme responsible for N-terminal acetylation of histones H2A and H4, which has been previously implicated with metabolic-associated conditions such as age-dependent hepatic steatosis and calorie-restriction-mediated longevity. RESULTS: Using metabolomic and lipidomic approaches, we found that depletion of NAA40 in murine hepatocytes leads to significant increase in intracellular acetyl-CoA levels, which associates with enhanced lipid synthesis demonstrated by upregulation in de novo lipogenesis genes as well as increased levels of diglycerides and triglycerides. Consistently, the increase in these lipid species coincide with the accumulation of cytoplasmic lipid droplets and impaired insulin signalling indicated by decreased glucose uptake. However, the effect of NAA40 on lipid droplet formation is independent of insulin. In addition, the induction in lipid synthesis is replicated in vivo in the Drosophila melanogaster larval fat body. Finally, supporting our results, we find a strong association of NAA40 expression with insulin sensitivity in obese patients. CONCLUSIONS: Overall, our findings demonstrate that NAA40 affects the levels of cellular acetyl-CoA, thereby impacting lipid synthesis and insulin signalling. This study reveals a novel path through which histone-modifying enzymes influence cellular metabolism with potential implications in metabolic disorders

How Gut Microbes Nurture Intestinal Stem Cells: A <i>Drosophila</i> Perspective

Host-microbiota interactions are key modulators of host physiology and behavior. Accumulating evidence suggests that the complex interplay between microbiota, diet and the intestine controls host health. Great emphasis has been given on how gut microbes have evolved to harvest energy from the diet to control energy balance, host metabolism and fitness. In addition, many metabolites essential for intestinal homeostasis are mainly derived from gut microbiota and can alleviate nutritional imbalances. However, due to the high complexity of the system, the molecular mechanisms that control host-microbiota mutualism, as well as whether and how microbiota affects host intestinal stem cells (ISCs) remain elusive. Drosophila encompasses a low complexity intestinal microbiome and has recently emerged as a system that might uncover evolutionarily conserved mechanisms of microbiota-derived nutrient ISC regulation. Here, we review recent studies using the Drosophila model that directly link microbiota-derived metabolites and ISC function. This research field provides exciting perspectives for putative future treatments of ISC-related diseases based on monitoring and manipulating intestinal microbiota

Μελέτη της επίδρασης του νευρογόνου γονιδίου neuralized της D.melanogaster στο μηχανισμό διακυτταρικής σηματοδότησης Notch

Tα νευρογόνα γονίδια, όπως αυτά που κωδικοποιούν τον υποδοχέα Notch και τον δεσμευτή Delta, παίζουν πολύ σημαντικό ρόλο στην διακυτταρική σηματοδότηση που καθορίζει την επιδερμική έναντι της νευρικής τύχης κατά την ανάπτυξη της D. melanogaster. Tο γονίδιο neuralized, ένα επιπλέον μέλος της οικογένειας των νευρογόνων γονιδίων, κωδικοποιεί μία πρωτεΐνη 754 αμινοξέων, της οποίας ο ρόλος δεν έχει διασαφηνιστεί πλήρως. O υποκυτταρικός εντοπισμός χιμαιρικών πρωτεϊνών του Neuralized με GFP ή myc στην κυτταρική μεμβράνη και στο κυτταρόπλασμα και όχι στον πυρήνα, όπως αρχικά πιστεύετο, σε συνδυασμό με την παρουσία ενός μοτίβου RING στο μόριο, που ίσως σχετίζεται με ουβικουϊτινυλίωση, υποδεικνύουν ότι η εν λόγω πρωτεΐνη λειτουργεί σε κάποιο ρυθμιστικό στάδιο στο μονοπάτι. Bιοχημικές και ιστολογικές μέθοδοι χρησιμοποιήθηκαν προκειμένου να διαπιστωθεί η επίδραση του neuralized σε βασικούς παράγοντες του σηματοδοτικού μονοπατιού, όπως ο υποδοχέας Notch και ο δεσμευτής του Delta. Aνάλυση πρωτεϊνικών εκχυλισμάτων με τη μέθοδο Western δείχνει ότι τα επίπεδα των πρωτεϊνών Delta και Notch αυξάνονται σε μεταλλαγές απώλειας λειτουργίας του γονιδίου neuralized σε έμβρυα, ενώ σε εκτοπική έκφραση του γονιδίου (με τα σύστημα UAS-Gal4) σε προνύμφες 3ου σταδίου, τα επίπεδα της πρωτεΐνης Delta ελαττώνονται. Eπιπλέον, παρουσία neuralized, παρατηρείται αλλαγή της κυτταρικής τοποθέτησης της πρωτεΐνης Delta και μεταφορά από την κυτταρική μεμβράνη σε κυστίδια αγνώστου ταυτότητας. Eπίσης, παρουσία neuralized, παρατηρείται αυξημένη σηματοδότηση μέσω Delta (σε πειράματα εκτοπικής συνέκφρασης Delta και neuralized), η οποία σχετίζεται με αυξημένη έκφραση κάτωθεν γονιδίων-στόχων του μονοπατιού, όπως το cut και το γονιδιακό σύμπλοκο E(spl). Συνεπώς, προτείνουμε ότι το neuralized επηρεάζει το Delta ή το Notch μετα-μεταγραφικά και οδηγεί σε ενίσχυση της σηματοδότησης