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An imbalance of protein homeostasis caused by external or internal stress in the endoplasmic reticulum triggers the initiation of signalling pathways downstream of the IRE1, ATF6 and PERK sensors to a translational or transcriptional adaptive response known as UPR (Unfolded Protein Response). According to the intensity and duration of stress, the dual function of the UPR leads to either cell adaptation or cell death. UPR pathways in cancer cells are often altered and generally lead to an adaptation to an hostile environment. As the UPR becomes an emerging therapeutic target due to its increasing contribution to various diseases, we describe in this review various strategies that have been developed to discover new compounds enabling to manipulate the magnitude of ER stress in the context of cancer., (© 2015 médecine/sciences – Inserm.)

When exposed to environmental stresses, cells activate defence mechanisms to adapt stress and inhibit apoptotic pathways leading to their survival. Stressed cells also reduce their general metabolism in part by inhibiting mRNA translation, thereby saving energy needed to repair stress-induced damages. Under stress conditions, the inhibition of mRNA translation occurs mainly at its initiation step through the phosphorylation of the translation initiation factor eIF2α. One of the four kinases known to phosphorylate eIF2α is heme-regulated inhibitor (HRI). The activation of HRI occurs under conditions of heme deficiency, oxidative stress and treatment with anti-cancer drugs such as proteasome inhibitors. In this article, we discuss the role of HRI in promoting cell resistance to stress-mediated apoptosis., (© 2014 médecine/sciences – Inserm.)

The endoplasmic reticulum (ER) is the first compartment in the secretory pathway. In the ER, proteins fold into their native configuration and are modified by post-translational modifications. Perturbations that alter ER homeostasis therefore disrupt folding and lead to the accumulation of unfolded proteins. These perturbations include modifications of Ca2+ homeostasis, increased demand for protein folding due to elevated synthesis of proteins in specialized cells or expression of a mutant misfolded protein. To limit accumulation of unfolded proteins, the cells have developed a specialized pathway : the unfolded protein response (UPR). UPR involves the activation of three transmembrane proteins of the ER : the PKR-like ER protein kinase (PERK), the activating transcription factor 6 (ATF6) and the inositol requiring enzyme 1 (IRE-1). The activation of all three components of the UPR depends on the dissociation of the luminal chaperone BiP/GRP78 from the luminal part of these proteins. Once activated, these pathways down-regulate protein synthesis through the phosphorylation of eiF2 (eucaryotic translation initiation factor 2) and up-regulate the transcription of genes which encode ER chaperones, protein folding enzymes and components of the ER-associated degradation system (ERAD). Growing evidences indicate that UPR signaling plays critical roles in nutrient sensing, differentiation of secretory cells such as pancreatic b cell and antibody producing plasma cells, glucose homeostasis and in the development of pathologies linked to accumulation of aggregated proteins.

15 % of human cancers have virus origin, meaning that viruses are the second cause of cancers after tabagism. The knowledge of antiviral mechanisms is essential for treatment and prevention of infection evolution towards cancers. Interferons (IFNs) are a large family of multifunctional cytokines. They are involved in regulation of cell growth and modulation of immune response. But, all these functions seem to converge toward the most important of them : the antiviral activity. IFN secretion is the first event induced by viral infection, and will act on specific receptors on neighbour cells and prevent their infection by inducing numbers of antiviral genes. Although few of them are well known like the PKR, the 2-5OAS/RNase L pathway and the Mx proteins, many others need extensive studies to understand the wide range of IFN effect. Viruses have evolved to circumvent the IFN antiviral activity, and are able not only to divert the cellular machinery but also to lure the antiviral mechanisms of the host cell. The purpose of this review is to describe the many antiviral pathways and proteins induced by IFNs and to summarize the strategies of viral escape.