Committing curriculum time to science literacy: The benefits from science based media resources

Kaposi sarcoma-associated herpesvirus (KSHV) is linked with the development of Kaposi sarcoma and the B lymphocyte disorders primary effusion lymphoma (PEL) and multi-centric Castleman disease. T cell immunity limits KSHV infection and disease, however the virus employs multiple mechanisms to inhibit efficient control by these effectors. Thus KSHV-specific CD4+ T cells poorly recognize most PEL cells and even where they can, they are unable to kill them. To make KSHV-infected cells more sensitive to T cell control we treated PEL cells with the thymidine analogue azidothymidine (AZT), which sensitizes PEL lines to Fas-ligand and TRAIL challenge; effector mechanisms which T cells use. PELs co-cultured with KSHV-specific CD4+ T cells in the absence of AZT showed no control of PEL outgrowth. However in the presence of AZT PEL outgrowth was controlled in an MHC-restricted manner. To investigate how AZT sensitizes PELs to immune control we first examined BJAB cells transduced with individual KSHV-latent genes for their ability to resist apoptosis mediated by stimuli delivered through Fas and TRAIL receptors. This showed that in addition to the previously described vFLIP protein, expression of vIRF3 also inhibited apoptosis delivered by these stimuli. Importantly vIRF3 mediated protection from these apoptotic stimuli was inhibited in the presence of AZT as was a second vIRF3 associated phenotype, the downregulation of surface MHC class II. Although both vFLIP and vIRF3 are expressed in PELs, we propose that inhibiting vIRF3 function with AZT may be sufficient to restore T cell control of these tumor cells

NFATc1 Regulation of TRAIL Expression in Human Intestinal Cells

TNF-related apoptosis-inducing ligand (TRAIL; Apo2) has been shown to promote intestinal cell differentiation. Nuclear factor of activated T cells (NFAT) participates in the regulation of a variety of cellular processes, including differentiation. Here, we examined the role of NFAT in the regulation of TRAIL in human intestinal cells. Treatment with a combination of phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187 (Io) increased NFAT activation and TRAIL expression; pretreatment with the calcineurin inhibitor cyclosporine A (CsA), an antagonist of NFAT signaling, diminished NFAT activation and TRAIL induction. In addition, knockdown of NFATc1, NFATc2, NFATc3, and NFATc4 blocked PMA/Io increased TRAIL protein expression. Expression of NFATc1 activated TRAIL promoter activity and increased TRAIL mRNA and protein expression. Deletion of NFAT binding sites from the TRAIL promoter did not significantly abrogate NFATc1-increased TRAIL promoter activity, suggesting an indirect regulation of TRAIL expression by NFAT activation. Knockdown of NFATc1 increased Sp1 transcription factor binding to the TRAIL promoter and, importantly, inhibition of Sp1, by chemical inhibition or RNA interference, increased TRAIL expression. These studies identify a novel mechanism for TRAIL regulation by which activation of NFATc1 increases TRAIL expression through negative regulation of Sp1 binding to the TRAIL promoter

Gewerkschaften und neue internationale Arbeitsteilung

Fohrbeck S. Gewerkschaften und neue internationale Arbeitsteilung. Sozialwissenschaftliche Studien zu internationalen Problemen ; 75. Saarbrücken: Breitenbach; 1982

miR-23a functions downstream of NFATc3 to regulate cardiac hypertrophy

Cardiac hypertrophy is accompanied by maladaptive cardiac remodeling, which leads to heart failure or sudden death. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that mediate posttranscriptional gene silencing. Recent studies show that miRNAs are involved in the pathogenesis of hypertrophy, but their signaling regulations remain to be understood. Here, we report that miR-23a is a pro-hypertrophic miRNA, and its expression is regulated by the transcription factor, nuclear factor of activated T cells (NFATc3). The results showed that miR-23a expression was up-regulated upon treatment with the hypertrophic stimuli including isoproterenol and aldosterone. Knockdown of miR-23a could attenuate hypertrophy, suggesting that miR-23a is able to convey the hypertrophic signal. In exploring the molecular mechanism by which miR-23a is up-regulated, we identified that NFATc3 could directly activate miR-23a expression through the transcriptional machinery. The muscle specific ring finger protein 1, an anti-hypertrophic protein, was identified to be a target of miR-23a. Its translation could be suppressed by miR-23a. Our data provide a model in which the miRNA expression is regulated by the hypertrophic transcriptional factor