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BACKGROUND: Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER)-localised protein and member of the leucine zipper family of transcription factors. Best known for its role in transducing signals linked to stress to the endoplasmic reticulum, the 50 kDa activated form of ATF6 is now emerging as a major regulator of organogenesis and tissue homeostasis. Responsible for the correct folding, secretion and membrane insertion of a third of the proteome in eukaryotic cells, the ER encompasses a dynamic, labyrinthine network of regulators, chaperones, foldases and cofactors. Such structures are crucial to the extensive protein synthesis required to undergo normal development and maintenance of tissue homeostasis. When an additional protein synthesis burden is placed on the ER, ATF6, in tandem with ER stress transducers inositol requiring enzyme 1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK), slows the pace of protein translation and induces the production of stress-reducing chaperones and foldases.MAIN TEXT: In the context of development and tissue homeostasis, however, distinct cellular impacts have been attributed to ATF6. Drawing on data published from human, rodent, fish, goat and bovine research, this review first focuses on ATF6-mediated regulation of osteo- and chondrogenesis, ocular development as well as neuro- and myelinogenesis. The purported role of ATF6 in development of the muscular and reproductive systems as well as adipo- and lipogenesis is then described. With relevance to cardiac disease, cancer and brain disorders, the importance of ATF6 in maintaining tissue homeostasis is the subject of the final section.CONCLUSION: In conclusion, the review encourages further elucidation of ATF6 regulatory operations during organogenesis and tissue homeostasis, to spawn the development of ATF6-targeted therapeutic strategies.

Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis., TUSC3 resides on chromosome 8p which is frequently deleted in advanced stage tumors. Here, the authors show that TUSC3 loss mediated by miR-224/-520c promotes NSCLC metastasis where it enhances ATF-6α-dependent UPR and HRD-1 dependent ERAD, which in turn suppress p53-NM23H1/2 tumor suppressor pathway.

Item does not contain fulltext Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2alpha. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death. 01 november 2011