Extracellular ATP activates transcription factor NFAT in mouse microglial cells

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Stimulation of serum- and glucocorticoid-regulated kinase-1 gene expression by endothelin-1

The serum- and glucocorticoid-regulated kinase-1 (SGK1) participates in the regulation of sodium homeostasis and blood pressure by mineralocorticoids. Aldosterone rapidly induces SGK1 transcription, which contributes to the activation of renal epithelial sodium channels. Another important regulator of blood pressure is the vasoactive hormone endothelin-1 (ET-1) that is systemically upregulated in chronic renal failure. In the present study, we investigated whether ET-1 modulates SGK1 expression, and thereby might explain some of its hypertensive effects. As assessed by real-time PCR analysis, ET-1 triggered the rapid increase of SGK1 mRNA levels in A-10 smooth muscle cells and also in intact aortas of adult rats. In A-10 cells transcriptional activation was associated with a more than 6-fold upregulation of SGK1 protein expression and in similar range as found after treatment with aldosterone. A stimulatory effect of ET-1 was not only observed in isolated cells, but also in an animal model. Upon subtotal neph rectomy (SNX) of rats, myocardial ET-1 levels strongly increased, which was followed by a more than 2-fold induction of SGK1 expression in the left ventricle. The myocardial upregulation of SGK1 was completely abrogated by a specific ET(A) receptor antagonist, thereby substantiating the in vivo role of ET-1 in SGK1 expression. Thus, these data demonstrate that ET-1 increases expression of SGK1 in vivo and in vitro, and therefore indicate that SGK1 upregulation might be involved in ET-1-dependent regulation of blood pressure and cardiac modelling during mild renal failure

Caspase Activation by Adenovirus E4orf4 Protein Is Cell Line Specific and Is Mediated by the Death Receptor Pathway

Adenovirus E4orf4 protein has been shown to induce transformed cell-specific, protein phosphatase 2A-dependent, and p53-independent apoptosis. It has been further reported that the E4orf4 apoptotic pathway is caspase-independent in CHO cells. Here, we show that E4orf4 induces caspase activation in the human cell lines H1299 and 293T. Caspase activation is required for apoptosis in 293T cells, but not in H1299 cells. Dominant negative mutants of caspase-8 and the death receptor adapter protein FADD/MORT1 inhibit E4orf4-induced apoptosis in 293T cells, suggesting that E4orf4 activates the death receptor pathway. Cytochrome c is released into the cytosol in E4orf4-expressing cells, but caspase-9 is not required for induction of apoptosis. Furthermore, E4orf4 induces accumulation of reactive oxygen species (ROS) in a caspase-8- and FADD/MORT1-dependent manner, and inhibition of ROS generation by 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron) inhibits E4orf4-induced apoptosis. Thus, our results demonstrate that E4orf4 engages the death receptor pathway to generate at least part of the molecular events required for E4orf4-induced apoptosis