The NHE1 Na+/H+ exchanger recruits ezrin/radixin/moesin proteins to regulate Akt-dependent cell survival.

Apoptosis results in cell shrinkage and intracellular acidification, processes opposed by the ubiquitously expressed NHE1 Na(+)/H(+) exchanger. In addition to mediating Na(+)/H(+) transport, NHE1 interacts with ezrin/radixin/moesin (ERM), which tethers NHE1 to cortical actin cytoskeleton to regulate cell shape, adhesion, motility, and resistance to apoptosis. We hypothesize that apoptotic stress activates NHE1-dependent Na(+)/H(+) exchange, and NHE1-ERM interaction is required for cell survival signaling.

Pleiotropic effects of a chromosome 3 locus on speech-sound disorder and reading.

Speech-sound disorder (SSD) is a complex behavioral disorder characterized by speech-sound production errors associated with deficits in articulation, phonological processes, and cognitive linguistic processes. SSD is prevalent in childhood and is comorbid with disorders of language, spelling, and reading disability, or dyslexia. Previous research suggests that developmental problems in domains associated with speech and language acquisition place a child at risk for dyslexia.

A WT1 co-regulator controls podocyte phenotype by shuttling between adhesion structures and nucleus.

Glomerular podocyte differentiation state is critical for filtration barrier function and is regulated by WT1, a zinc finger transcription factor. A yeast two-hybrid assay identified a novel, WT1-interacting protein (WTIP) that maps to human chromosome 19q13.1, a region with genes linked to familial focal segmental glomerulosclerosis.

EphA kinase activation regulates HGF-induced epithelial branching morphogenesis.

Eph kinases and their ephrin ligands are widely expressed in epithelial cells in vitro and in vivo. Our results show that activation of endogenous EphA kinases in Madin-Darby canine kidney (MDCK) cells negatively regulates hepatocyte growth factor/scatter factor (HGF)-induced branching morphogenesis in collagen gel. Cotreatment with HGF and ephrin-A1 reduced sprouting of cell protrusions, an early step in branching morphogenesis.

Nucleic acid-based techniques for post-transcriptional regulation of molecular targets.

Purpose Of Review: Messenger RNA, transfer RNA and ribosomal RNA were defined long ago as essential components for transmission of genetic code from DNA. However, there are many other, less commonly recognized RNAs, such as ribozymes and small interfering RNAs, which are distinguished by their ability to inhibit RNA function. This review describes the basic molecular concepts and potential therapeutic applications of RNA inhibition by a variety of molecules, including ribozymes, antisense oligonucleotides, aptamers and small interfering RNAs.

Chemometrical classification of ephrin ligands and Eph kinases using GRID/CPCA approach.

Eph receptor tyrosine kinases are divided on two subfamilies based on their affinity for ephrin ligands and play a crucial role in the intercellular processes such as angiogenesis, neurogenesis, and carcinogenesis. As such, Eph kinases represent potential targets for drug design, which requires the knowledge of structural features responsible for their specific interactions. To overcome the existing gap between available sequence and structure information we have built 3D models of eight ephrins and 13 Eph kinase ligand-binding domains using homology modeling techniques.

Kidney disease, genotype and the pathogenesis of vasculopathy.

Purpose Of Review: The two leading causes of end-stage renal disease in the United States are diabetes mellitus and hypertensive nephrosclerosis, accounting for over two-thirds of all cases. In many patients both diseases are associated with small- and large-vessel disease, commonly attributed to hypertension or accelerated atherosclerosis. Recent investigations, however, have suggested that renal large-vessel and microvascular disease may be independent contributors to progressive kidney failure.

Approaches to understanding susceptibility to nephropathy: from genetics to genomics.

The incidence of end-stage renal disease (ESRD) is increasing worldwide despite efforts to slow the progression of chronic renal failure (CRF) by controlling blood pressure and hyperglycemia. Two available therapies for ESRD, dialysis and transplantation, are expensive and are at best palliative. Recently, data from several laboratories have demonstrated that ESRD is under substantial genetic control, and efforts to identify these genetic determinants are underway.

Microcyst formation and HIV-1 gene expression occur in multiple nephron segments in HIV-associated nephropathy.

Tubular microcyst formation is a prominent histopathologic feature of HIV-associated nephropathy (HIVAN), but its pathogenesis is unknown. HIV-1 has recently been shown to infect renal tubular epithelial cells in patients with HIVAN. In addition, HIV-1 gene expression in renal epithelial cells has been shown to cause a renal disease that is identical to HIVAN in HIV-1 transgenic mice.

Increased synthesis of thromboxane A(2) and expression of procoagulant activity by monocytes in response to arachidonic acid in diabetes mellitus.

Thromboxane A(2) (TXA(2)) synthesis and expression of procoagulant activity (PCA) were investigated in mononuclear cells and monocytes prepared from a control and a Type 2 diabetic group. Monocytes from the diabetic group produced 2.10+/-0.

Apoptosis and JNK activation are differentially regulated by Fas expression level in renal tubular epithelial cells.

Background: In chronic renal disease, renal tubular epithelial cell (RTC) Fas expression is up-regulated, leading to apoptotic RTC deletion and tubular atrophy. In vitro, cytokine- or hypoxia-induced up-regulation of Fas expression is associated with RTC apoptosis. In contrast, constitutively expressed, low level RTC Fas does not mediate apoptosis, suggesting that Fas may be coupled to expression level-dependent RTC signaling pathways.

Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway.

Interactions between Eph receptor tyrosine kinases (RTKs) and membrane-anchored ephrin ligands critically regulate axon pathfinding and development of the cardiovascular system, as well as migration of neural cells. Similar to other RTKs, ligand-activated Eph kinases recruit multiple signalling and adaptor proteins, several of which are involved in growth regulation. However, in contrast to other RTKs, activation of Eph receptors fails to promote cell proliferation or to transform rodent fibroblasts, indicating that Eph kinases may initiate signalling pathways that are distinct from those transmitted by other RTKs.

Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4.

As with many complex genetic diseases, genome scans for prostate cancer have given conflicting results, often failing to provide replication of previous findings. One factor contributing to the lack of consistency across studies is locus heterogeneity, which can weaken or even eliminate evidence for linkage that is present only in a subset of families. Currently, most analyses either fail to account for locus heterogeneity or attempt to account for it only by partitioning data sets into smaller and smaller portions.

Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation.

Interactions between receptor tyrosine kinases of the Eph family and their ligands, ephrins, are implicated in establishment of organ boundaries and repulsive guidance of cell migration during development, but the mechanisms by which this is achieved are unclear. Here we show that activation of endogenous EphA2 kinase induces an inactive conformation of integrins and inhibits cell spreading, migration and integrin-mediated adhesion. Moreover, EphA2 is constitutively associated with focal-adhesion kinase (FAK) in resting cells.

Isolation of high-affinity peptide antagonists of 14-3-3 proteins by phage display.

The 14-3-3 proteins interact with diverse cellular molecules involved in various signal transduction pathways controlling cell proliferation, transformation, and apoptosis. To aid our investigation of the biological function of 14-3-3 proteins, we have set out to identify high-affinity antagonists. By screening phage display libraries, we have identified a set of peptides which bind 14-3-3 proteins.

Pathways of HERG inactivation.

The rapid, repolarizing K(+) current in cardiomyocytes (I(Kr)) has unique inwardly rectifying properties that contribute importantly to the downstroke of the cardiac action potential. The human ether-à-go-go-related gene (HERG) expresses a macroscopic current virtually identical to I(Kr), but a description of the single-channel properties that cause rectification is lacking. For this reason we measured single-channel and macropatch currents heterologously expressed by HERG in Xenopus oocytes.

Semantics, inflammation, cytokines and common sense.

Semantic evaluation of some of the terms we regularly employ--inflammation, anti-inflammatory, pro-inflammatory, anti-inflammatory drugs, cytokines, homeostasis and stress--raises concerns about their precise meanings and about their mechanistic implications. Semantic imprecision may have undesirable conceptual consequences.

Blockade of HERG and Kv1.5 by ketoconazole.

Ketoconazole, a widely used fungicide in patients, has been associated with Q-T prolongation and torsade de pointes when co-administered with terfenadine (Seldane). Both compounds use the same cytochrome-P450 metabolic pathway, resulting in an increase in plasma concentration of terfenadine. We previously showed that terfenadine blocked HERG (Human Ether-a-Gogo Related Gene), an important component of the repolarizing cardiac delayed rectifier IK with concentration needed to obtain 50% of the block (IC50) in the therapeutic range (300 nM).

Fas-dependent fratricidal apoptosis is a mechanism of tubular epithelial cell deletion in chronic renal failure.

Renal tubular atrophy predicts a poor prognosis in chronic renal failure, but the molecular mechanisms regulating this process remain unknown. Because the Fas apoptosis pathway has recently been implicated in disease pathogenesis and Fas is expressed in the kidney, we hypothesized that Fas-mediated apoptosis of renal tubule epithelial cells (RTC) contributes to tubular atrophy in chronic renal failure. In vivo, immunohistochemical analyses of renal sections from two murine models of progressive renal disease revealed coordinate increases in RTC Fas expression and apoptosis compared with tissue sections from age-matched control kidneys.

Mechanism of lidocaine block of late current in long Q-T mutant Na+ channels.

Inherited long Q-T syndrome is a ventricular arrhythmia associated with delayed repolarization and the risk of sudden death. The chromosome 3-linked form of the disease (LQT3) is associated with mutations in the cardiac Na+ channel (N1325S or R1644H; or deletion of residues 1,505-1,507, delta KPQ) that increase late inward currents and may cause delayed repolarization. Late currents arise from dispersed reopenings (N1325S and R1644H) or from reopenings combined with prolonged bursts (delta KPQ).

Concomitant and hormonally regulated expression of trp genes in bovine aortic endothelial cells.

Recent findings have suggested that the vertebrate trp family of channel proteins is the structural basis for Ca2+ influx through the capacitative calcium entry (CCE) pathway. We have discerned, in bovine aortic endothelial cells, the concomitant expression of four such vertebrate genes: trp-1 (two splice variants), trp-3, trp-4 and trp-5. Exogenous hormones rendered dynamic effects on the transcript levels of these genes.

Interactions among inactivating and noninactivating Kvbeta subunits, and Kvalpha1.2, produce potassium currents with intermediate inactivation.

Experiments were carried out to determine whether coinjection of Kvalpha1.2 with inactivating and noninactivating Kvbeta subunits would produce currents with intermediate kinetics and channel complexes containing a mixture of these subunits. Upon coexpression with a saturating amount of Kvbeta1.

Separable Kvbeta subunit domains alter expression and gating of potassium channels.

Kvbeta subunits have been shown to affect kinetic properties of voltage-gated K+ channel Kv1alpha subunits and increase the number of cell surface dendrotoxin-binding sites when coexpressed with Kv1. 2. Here, we show that Kvbeta1.

Angiotensin II activates the beta 1 isoform of phospholipase C in vascular smooth muscle cells.

Vascular smooth muscle cells (VSMC) contribute to the pathophysiology of hypertension through cell growth and contraction, and phospholipase C (PLC) is a critical effector enzyme in growth factor and vasoconstrictor signaling. There is indirect evidence that angiotensin II (ANG II) receptors are linked to the PLC-beta isoform signaling pathways. However, recent studies suggest that PLC-beta isoforms may not be expressed in VSMC.

Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide.

Background: The human ether-a-go-go-related gene (HERG) is one locus for the hereditary long-QT syndrome. A hypothesis is that HERG produces the repolarizing cardiac potassium current IKr with the consequence that mutations in HERG prolong the QT interval by reducing IKr. The elementary properties of HERG are unknown, and as a test of the hypothesis that HERG produces IKr, we compared their elementary properties.