Le stress du réticulum endoplasmique : adaptation et toxicité

La majorité des protéines sécrétées et membranaires sont synthétisées dans le réticulum endoplasmique où elles sont repliées et assemblées avant d’être transportées. Dans certaines conditions cellulaires, des protéines de conformation anormale s’accumulent dans le réticulum endoplasmique et induisent la réponse UPR (unfolded protein response). Chez les mammifères, la réponse UPR inclut une activation de la transcription de gènes cibles et une profonde inhibition de la traduction, ce qui augmente les capacités de repliement et de dégradation et limite l’arrivée de nouvelles protéines dans le réticulum endoplasmique. Les voies de signalisation intracellulaire déclenchées par ce stress sont très originales : elles activent des protéines transmembranaires du réticulum endoplasmique et mettent en jeu un épissage non conventionnel d’un ARN messager. Lorsque cette réponse adaptative est insuffisante, une réponse apoptotique est déclenchée. Le stress du réticulum endoplasmique et/ou la mort cellulaire parfois induite lors de la réponse UPR semblent intervenir dans la physiopathologie de certaines maladies comme le déficit en α1-antitrypsine et la maladie de Parkinson juvénile à transmission autosomique récessive

Stabilization of IGFBP-1 mRNA by ethanol in hepatoma cells involves the JNK pathway

International audienceBACKGROUND/AIMS: Insulin-like growth factor-binding protein-1 (IGFBP-1) modulates cell growth and metabolism in a variety of physiopathological conditions. The aim of this study was to determine the molecular mechanisms involved in IGFBP-1 upregulation by ethanol. METHODS: We studied IGFBP-1 regulation by ethanol at the protein, mRNA and gene promoter levels in the human hepatocarcinoma cell line, HepG2, which does not express significantly ethanol-metabolizing enzymes. RESULTS: Ethanol (35-150mM) induced the IGFBP-1 mRNA and protein up to 5-fold in a dose-dependent manner. A similar effect was observed using primary cultures of human hepatocytes. Various inhibitors of ethanol metabolism and the antioxidant N-acetylcysteine did not prevent ethanol effects. While ethanol did not modify the IGFBP-1 gene promoter activity, it elicited a 2- to 3-fold increase in IGFBP-1 mRNA half-life and this stabilization required the 5' and the 3' untranslated mRNA region. Ethanol triggered a rapid activation of c-Jun N-terminal Kinase (JNK) in HepG2 cells and IGFBP-1 induction was significantly decreased by a specific inhibitor of JNK. CONCLUSIONS: This study reveals a novel pathway of gene regulation by alcohol which involves the activation of JNK and the consequent mRNA stabilization

T-cadherin supports angiogenesis and adiponectin association with the vasculature in a mouse mammary tumor model

T-cadherin delineates endothelial, myoepithelial, and ductal epithelial cells in the normal mouse mammary gland, and becomes progressively restricted to the vasculature during mammary tumorigenesis. To test the function of T-cadherin in breast cancer, we inactivated the T-cadherin (Cdh13) gene in mice and evaluated tumor development and pathology after crossing the mutation into the mouse mammary tumor virus (MMTV)-polyoma virus middle T (PyV-mT) transgenic model. We report that T-cadherin deficiency limits mammary tumor vascularization and reduces tumor growth. Tumor transplantation experiments confirm the stromal role of T-cadherin in tumorigenesis. In comparison with wild-type MMTV-PyV-mT controls, T-cadherin-deficient tumors are pathologically advanced and metastasize to the lungs. T-cadherin is a suggested binding partner for high molecular weight forms of the circulating, fat-secreted hormone adiponectin. We discern adiponectin in association with the T-cadherin-positive vasculature in the normal and malignant mammary glands and report that this interaction is lost in the T-cadherin null condition. This work establishes a role for T-cadherin in promoting tumor angiogenesis and raises the possibility that vascular T-cadherin-adiponectin association may contribute to the molecular cross-talk between tumor cells and the stromal compartment in breast cancer

2,3,7,8-Tetrachlorodibenzo-p-Dioxin Counteracts the p53 Response to a Genotoxicant by Upregulating Expression of the Metastasis Marker AGR2 in the Hepatocarcinoma Cell Line HepG2

International audienceTCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is an environmental pollutant which binds the aryl hydrocarbon receptor (AhR), a transcription factor that triggers variousbiological responses. In this study, we show that TCDD treatment counteracts the p53 activation elicited by a genotoxic compound, etoposide, in the human hepatocarcinoma cell line HepG2 and we delineated the mechanisms of this interaction. Using siRNA knock-down experiments, we found that the newly described metastasis marker, anterior gradient-2 (AGR2), is involved in this effect. Both AGR2 mRNA and protein levels were increased (6-and 4-fold, respectively) by TCDD treatment and this effect was mediated by the AhR receptor. The half-life of AGR2 mRNA was unchanged by TCDD treatment. Analysis of the promoter of the AGR2 gene revealed 3 putative xenobiotic responsive elements (XRE) in the proximal 3.5 kb promoter. Transient transfection of HepG2 cells by the Gaussia luciferase reporter gene driven by various deleted and mutated fragments of the promoter indicated that only the most proximal XRE was active. These results suggest that AhR ligands such as TCDD may contribute to tumour progression by inhibiting p53 regulation by genotoxicants via the increased expression of the metastasis marker AGR2

INDUCTION OF THE RAS ACTIVATOR SON OF SEVENLESS 1 BY ENVIRONMENTAL POLLUTANTS MEDIATES THEIR EFFECTS ON CELLULAR PROLIFERATION

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