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After more than twenty years of research, the molecular events of apoptotic cell death can be succinctly stated; different pathways, activated by diverse signals, increase the activity of proteases called caspases that rapidly and irreversibly dismantle condemned cell by cleaving specific substrates. In this time the ideas that apoptosis protects us from tumourigenesis and that cancer chemotherapy works by inducing apoptosis also emerged. Currently, apoptosis research is shifting away from the intracellular events within the dying cell to focus on the effect of apoptotic cells on surrounding tissues. This is producing counterintuitive data showing that our understanding of the role of apoptosis in tumourigenesis and cancer therapy is too simple, with some interesting and provocative implications. Here, we will consider evidence supporting the idea that dying cells signal their presence to the surrounding tissue and, in doing so, elicit repair and regeneration that compensates for any loss of function caused by cell death. We will discuss evidence suggesting that cancer cell proliferation may be driven by inappropriate or corrupted tissue-repair programmes that are initiated by signals from apoptotic cells and show how this may dramatically modify how we view the role of apoptosis in both tumourigenesis and cancer therapy.
Wesch D, Althaus M, Miranda P, Cruz-Muros I, Fronius M, Gonzalez-Hernandez T, Clauss WG, de la Rosa DA, Giraldez T. Differential N termini in epithelial Na+ channel delta-subunit isoforms modulate channel trafficking to the membrane. Am J Physiol Cell Physiol 302: C868-C879, 2012. First published December 7, 2011; doi: 10.1152/ajpcell.00255.2011.-The epithelial Na+ channel (ENaC) is a heteromultimeric ion channel that plays a key role in Na+ reabsorption across tight epithelia. The canonical ENaC is formed by three analogous subunits, alpha, beta, and gamma. A fourth ENaC subunit, named delta, is expressed in the nervous system of primates, where its role is unknown. The human delta-ENaC gene generates at least two splice isoforms, delta(1) and delta(2), differing in the N-terminal sequence. Neurons in diverse areas of the human and monkey brain differentially express either delta(1) or delta(2), with few cells coexpressing both isoforms, which suggests that they may play specific physiological roles. Here we show that heterologous expression of delta(1) in Xenopus oocytes and HEK293 cells produces higher current levels than delta(2). Patch-clamp experiments showed no differences in single channel current magnitude and open probability between isoforms. Steady-state plasma membrane abundance accounts for the dissimilarity in macroscopic current levels. Differential trafficking between isoforms is independent of beta- and gamma-subunits, PY-motif-mediated endocytosis, or the presence of additional lysine residues in delta(2)-N terminus. Analysis of delta(2)-N terminus identified two sequences that independently reduce channel abundance in the plasma membrane. The delta(1) higher abundance is consistent with an increased insertion rate into the membrane, since endocytosis rates of both isoforms are indistinguishable. Finally, we conclude that delta-ENaC undergoes dynamin-independent endocytosis as opposed to alpha beta gamma-channels.
Disorders of the degradation of branched chain amino acids: what is new in clinics and laboratories?
(2012)
The vectorial transport of Na+ across epithelia is crucial for the maintenance of Na+ and water homeostasis in organs such as the kidneys, lung, or intestine. Dysregulated Na+ transport processes are associated with various human diseases such as hypertension, the salt-wasting syndrome pseudohypoaldosteronism type 1, pulmonary edema, cystic fibrosis, or intestinal disorders, which indicate that a precise regulation of epithelial Na+ transport is essential. Novel regulatory signaling molecules are gasotransmitters. There are currently three known gasotransmitters: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). These molecules are endogenously produced in mammalian cells by specific enzymes and have been shown to regulate various physiological processes. There is a growing body of evidence which indicates that gasotransmitters may also regulate Na+ transport across epithelia. This review will summarize the available data concerning NO, CO, and H2S dependent regulation of epithelial Na+ transport processes and will discuss whether or not these mediators can be considered as true physiological regulators of epithelial Na+ transport biology.
Molybdenum cofactor deficiency (MoCD) is a rare inherited metabolic disorder characterized by severe and progressive neurological damage mainly caused by the loss of sulfite oxidase activity. Elevated urinary levels of sulfite, thiosulfate, and S-sulfocysteine (SSC) are hallmarks in the diagnosis of MoCD and sulfite oxidase deficiency (SOD). Recently, a first successful treatment of a human MoCD type A patient based on a substitution therapy with the molybdenum cofactor precursor cPMP has been reported, resulting in nearly complete normalization of MoCD biomarkers. Knowing the rapid progression of the disease symptoms in nontreated patients, an early diagnosis of MoCD as well as a sensitive method to monitor daily changes in SSC levels, a key marker of sulfite toxicity, is crucial for treatment outcome. Here, we describe a fast and sensitive method for the analysis of SSC in human urine samples using high performance liquid chromatography (HPLC). The analysis is based on precolumn derivatization with O-phthaldialdehyde (OPA) and separation on a C18 reverse phase column coupled to UV detection. The method was extended to human serum analysis and no interference with endogenous amino acids was found. Finally, SSC values from 45 pediatric urine, 75 adult urine, and 24 serum samples from control individuals as well as MoCD patients are reported. Our method represents a cost-effective technique for routine diagnosis of MoCD and SOD, and can be used also to monitor treatment efficiency in those sulfite toxicity disorders on a daily basis.