Highlights d IPH5201 and IPH5301 block cell-borne and soluble CD39 and CD73, respectively d IPH5201 maintains immunogenic extracellular ATP d When used in combination with chemotherapy, IPH5201 promotes antitumor immunity d Targeting CD39 and CD73 synergistically promotes cancer patient T cell activation

Ferry A, Bonnieu A, Ollendorff V, Favier FB. REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy. Am J Physiol Endocrinol Metab 307: E983-E993, 2014. First published October 14, 2014 doi:10.1152/ajpendo.00234.2014.-REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wildtype (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoidinduced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy. regulated in development and DNA damage response 1; protein synthesis; mechanistic target of rapamycin; autophagy; glucocorticoids; proline-rich Akt substrate of 40 kDa

BackgroundSkeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a component of energy stress responses.ResultsUnexpectedly, we show here that REDD1 instead limits muscle loss during energetic stresses such as hypoxia and fasting by reducing glycogen depletion and AMPK activation. Indeed, we demonstrate that REDD1 is required to decrease O2 and ATP consumption in skeletal muscle via reduction of the extent of mitochondrial-associated endoplasmic reticulum membranes (MAMs), a central hub connecting energy production by mitochondria and anabolic processes. In fact, REDD1 inhibits ATP-demanding processes such as glycogen storage and protein synthesis through disruption of the Akt/Hexokinase II and PRAS40/mTORC1 signaling pathways in MAMs. Our results uncover a new REDD1-dependent mechanism coupling mitochondrial respiration and anabolic processes during hypoxia, fasting, and exercise.ConclusionsTherefore, REDD1 is a crucial negative regulator of energy expenditure that is necessary for muscle adaptation during energetic stresses. This present study could shed new light on the role of REDD1 in several pathologies associated with energetic metabolism alteration, such as cancer, diabetes, and Parkinson’s disease.Electronic supplementary materialThe online version of this article (10.1186/s12915-018-0525-4) contains supplementary material, which is available to authorized users.

Purpose: Receptor-interacting protein of 140 kDa (RIP140) is a transcriptional cofactor for nuclear receptors involved in reproduction and energy homeostasis. Our aim was to investigate its role in the regulation of E2F1 activity and target genes both in breast cancer cell lines and in tumor biopsies.Experimental Design: Glutathione S-transferase pull-down assays, coimmunoprecipitation experiments, and chromatin immunoprecipitation analysis were used to evidence interaction between RIP140 and E2F1. The effects of RIP140 expression on E2F1 activity were determined using transient transfection and quantification of E2F target mRNAs by quantitative real-time PCR. The effect on cell cycle was assessed by fluorescence-activated cell sorting analysis on cells overexpressing green fluorescent protein-tagged RIP140. A tumor microarray data set was used to investigate the expression of RIP140 and E2F1 target genes in 170 breast cancer patients.Results: We first evidenced the complex interaction between RIP140 and E2F1 and showed that RIP140 represses E2F1 transactivation on various transiently transfected E2F target promoters and inhibits the expression of several E2F1 target genes (such as CCNE1 and CCNB2). In agreement with a role for RIP140 in the control of E2F activity, we show that increasing RIP140 levels results in a reduction in the proportion of cells in S phase in various human cell lines. Finally, analysis of human breast cancers shows that low RIP140 mRNA expression was associated with high E2F1 target gene levels and basal-like tumors.Conclusion: This study shows that RIP140 is a regulator of the E2F pathway, which discriminates luminal-and basal-like tumors, emphasizing the importance of these regulations for a clinical cancer phenotype. Clin Cancer Res; 16(11); 2959-70. ©2010 AACR.Cell cycle control is a fundamental process that governs cell proliferation and is frequently altered during tumorigenesis. E2Fs and their heterodimer partners (DP) are central regulators of cell cycle progression and directly regulate the expression of a broad spectrum of genes involved, for instance, in cell cycle regulation, DNA replication and repair, apoptosis, differentiation, or development (1, 2).E2F1, which was discovered as a protein promoting the transition to S phase, was the founding member of the E2F family, which comprises eight members in mammals. Among this family, some were initially presented as "activator E2Fs" (E2F1, E2F2, and E2F3), whereas the other members were mostly known as transcription repressors, although this classification now seemed too simplistic (reviewed in ref. 2 and references therein). E2F transcriptional activity was shown to be regulated by a large number of coactivators or corepressors, including the so-called pocket proteins, which form the retinoblastoma (RB) tumor suppressor family (pRB, together with the related proteins p107 and p130; ref. 3). RB attenuates E2F action by recruiting transcriptional corepressors such as histone deacetylases to E2F-regulated promoters, thus med...