Inhibition of ER stress-mediated apoptosis in macrophages by nuclear-cytoplasmic relocalization of eEF1A by the HIV-1 Nef protein

HIV-1 Nef protein has key roles at almost all stages of the viral life cycle. We assessed the role of the Nef/eEF1A (eukaryotic translation elongation factor 1-alpha) complex in nucleocytoplasmic shuttling in primary human macrophages. Nuclear retention experiments and inhibition of the exportin-t (Exp-t) pathway suggested that cytoplasmic relocalization of eEF1A, mediated by Exp-t, occurs in Nef-treated monocyte-derived macrophages (MDMs). We observed the presence of tRNA in the Nef/eEF1A complexes. Nucleocytoplasmic relocalization of the Nef/eEF1A complexes prevented stress-induced apoptosis of MDMs treated with brefeldin-A. Blockade of stress-induced apoptosis of MDMs treated with HIV-1 Nef resulted from enhanced nucleocytoplasmic transport of eEF1A with decreased release of mitochondrial cytochrome c, and from increased tRNA binding to cytochrome c, ultimately leading to an inhibition of caspase activation. Our results indicate that HIV-1 Nef, through the nucleocytoplasmic relocalization of eEF1A and tRNAs, enhances resistance to stress-induced apoptosis in primary human macrophages

Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkBa

The NF-kappa B/Rel family of transcription factors regulates wide variety of genes whose products play a fundamental role in inflammatory and immune responses. The implication of NF-kappa B/Rel proteins and their I kappa B regulatory subunits in the control of cellular growth and oncogenesis, was suggested by the induction of fatal lymphomas in birds by the v-rel oncoprotein, and the rearrangement and amplification of several genes encoding the NF-kappa B/Rel/I kappa B signal transduction factors in human malignancies, primarily of lymphoid origin. Hodgkin's disease (HD) is a lymphoma characterized by a low frequency of malignant Hodgkin and Reed-Sternberg (H/RS) cells in a reactive background of nonneoplastic cells. The peculiar activated phenotype of Hodgkin and Reed-Sternberg cells and their pattern of cytokine secretion are believed to be a consequence of constitutive activation of the NF-kappa B transcription factor. Here, we report the detection of mutations of the 1k Ba gene, in two HD-derived cell lines and in two out of eight biopsy samples from patients with relapsed Hodgkin's disease. The presence of defective I kappa B alpha is thus likely to explain the constitutive activation of NF-kappa B in these cells and suggests that I kappa B alpha is a tumour suppressor controlling the oncogenic activation of NF-kappa B in Hodgkin and Reed-Sternberg cells.</p

Atteinte ganglionnaire sentinelle et cancer de la prostate : quel impact sur la survie sans recidive ? À propos de 200 patients

International audienc

Between pathological prostate cancer lymph node and sentinel lymph node status : which one is the most informative?

International audienc