Cell Mol Life Sci Research Articles

Significant water absorption goes paracellular in kidney proximal tubules

it had been a fundamental dispute for several decades, whether water passes epithelia such as kidney proximal tubule or small intestine along the transcellular, paracellular, or both pathways. By discovery of the transmembranal aquaporin water channels (AQP), the molecular basis of the

THU0485 Muckle Wells Syndrome. A Case Series Characterized Genetically

BackgroundMuckle-Wells Syndrome(MWS) is a rare autosomal dominant disorderincluded inthe groupofhereditaryperiodic feversyndromes1. It is characterized byrecurrentand self-limitedepisodesof fever, rash, joint painand conjunctivitissince childhood. Sensorineural deafnessand amyloidosisappear lateranddetermine the disease prognosis2. It...

AB0066 Expression of NLRP3-inflammasome-related transcripts in peripheral blood of rheumatoid arthritis patients treated with infliximab

BackgroundThe assembly of a molecular scaffold termed the NLRP3-inflammasome complex, in monocytes, macrophages and dendritic cells, leads to the cleavage of pro-interleukin-1β(pro-IL-1β) into active IL-1β, a proinflammatory cytokine involved in...

The HDAC interaction network

The HDAC interaction network

Abnormal IgA1 O-Glycosylation in a Multi-ethnic population of IgA Nephropathy Patients in KwaZulu Natal, South Africa.

Abnormal IgA1 O-Glycosylation in a Multi-ethnic population of IgA Nephropathy Patients in KwaZulu Natal, South Africa.

HIF-1α induced by β-elemene protects human osteosarcoma cells from undergoing apoptosis

β-Elemene, isolated from more than 50 Chinese herbs and plants, has shown promising anticancer effects against a broad spectrum of tumors, such as lung, breast, prostate, cervical, colon and ovarian carcinomas (Wang et al. in Cell Mol Life Sci 62:881-893, 2005; Li et al. in Cell Mol Life Sci 62:894-904, 2005; J Pharm Pharmacol 62(8):1018-1027, 2010). But it has not reported in osteosarcoma cells. The aim of the present study is to investigate the antitumor effect of β-elemene on human osteosarcoma cancer cells and the molecular mechanism involved. β-Elemene inhibited the viability of human osteosarcoma cells in a dose-time-dependent manner. The suppression of cell viability was due to the induction of apoptosis. Our study also found that β-elemene treatment upregulated HIF-1α protein, which partially inhibits apoptosis. Knockdown of HIF-1α with small interfering RNA or co-treatment with the HIF-1α inhibitor YC-1 significantly enhanced the antitumor effects of β-elemene. Our study first found that β-elemene could increase the expression of HIF-1α through ROS and PI3K/Akt/mTor signaling pathway. And HIF-1α partially prevents human osteosarcoma cells from undergoing apoptosis. The anticancer effects of β-elemene was weakened by HIF-1α. So, we recognize that a combination of β-elemene with HIF-1α inhibitor might be a useful therapeutic option for osteosarcoma.

CFTR channel pharmacology: insight from a flock of clones. Focus on “Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101”

how do you identify drug-binding sites on an ion channel when you don't have a crystal structure? In the case of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a pivotal role in transepithelial ion transport, several approaches have been tried, including 1 ) targeting

Analysis of amyloid precursor protein function in Drosophila melanogaster

Amyloid precursor proteins (APPs) are evolutionary conserved from nematodes to man (Jacobsen and Iverfeldt in Cell Mol Life Sci 66:2299-2318, 2009) suggesting an important physiological function of these proteins. Human APP is a key factor in the pathogenesis of Alzheimer's Disease because its proteolytic processing results in the production of the neurotoxic Aβ-peptide, which accumulates in the amyloid plaques characteristic for this disease (Selkoe in Physiol Rev 81(2):741-766, 2001). However, the processing also leads to the production of several other fragments and the role of these products, as well as the function of the full-length protein is so far not well understood. The functional analysis of APP in vertebrates has been hampered by the fact that two close relatives, APLP1 and APLP2, exist and that knock-out mice for APP only show subtle defects. In contrast, invertebrates like Caenorhabditis elegans and Drosophila express only one APP-like protein but whereas a null mutation in the C. elegans APL-1 protein is lethal, flies lacking APPL (Amyloid Precursor Protein-like) are viable but show synaptic defects and behavioral abnormalities. Together with the analyses of flies that express APP proteins ectoptically or xenotopically, these studies show that APP proteins are involved in neuronal differentiation, neuritic outgrowth, and synapse formation. In addition, they play a role in long-term memory formation and maintaining brain integrity in adult flies.

No muscle atrophy without GSK-3β. Focus on “Glycogen synthase kinase-3β is required for the induction of skeletal muscle atrophy”

skeletal muscle atrophy is driven by an imbalance of protein synthesis and degradation, generally in favor of the latter. The ubiquitin-proteasome system (UPS) is commonly regarded as the major proteolytic system involved in breakdown of muscle protein under atrophy-inducing conditions ([6][1]), and

Dynamic communication between androgen and coactivator: Mutually induced conformational perturbations in androgen receptor ligand‐binding domain

The transcriptional activity of androgen receptor (AR) is regulated by the sequential binding of various ligands (e.g., dihydrotestosterone, DHT) and coactivators (e.g., SRC/p160) to the AR ligand binding domain (LBD) (Askew et al., J Biol Chem 2007; 282:25801-25816, Lee and Chang, Cell Mol Life Sci 2003;60:1613-1622). However, the synergism between the recruitments of coactivator (SRC 2-3) and ligand (such as DHT) to AR at atomic level remains unclear. Thus, in this work, extensive explicit-solvent molecular dynamics (MD) simulations on four independent trajectories, that is, AR-apo (unbound), DHT·AR, AR·SRC, and DHT·AR·SRC, are performed to investigate the potential communications between the two events in the AR transcriptional process. The MD simulations, analysis of the dynamical cross-correlation maps, comparisons of the binding energy, and thermodynamic analysis reveal a definite structural and functional link between Activation Function-2 (AF-2) surface and the ligand binding site influenced by the binding of ligand and coactivator to the LBD: (I) The DHT binding can increase the LBD volume to 753.0 A³ from its compact ligand-free state (372.1 A³), resulting in a group of helices (1, 2, 8, and loop 20) to move outward and exert added traction on the ligand binding pathway, which subsequently leads to rearrange the AF-2 region to well recruit the SRC; (II) Similarly, the SRC recruitment is also found to facilitate the ligand binding through transmitting a concomitant push-pull effort from the AF-2 surface to the DHT binding site, leading to the opening of entrance to the LBD formed by Val684, Met745, and Arg752, increase of the volume of binding pocket (896.4 A³) and stabilization of the dynamic structure of the LBD. These results, in a dynamic form, initially show a bidirectional structural and functional relay between the bound DHT and SRC that establishes AR functional potency.

Actin Polymerization Dynamics - Insights from In vitro TIRF Microscopy

Actin elongation is a bi-molecular reaction between monomeric actin (G-actin) and filamentous actin (F-actin), in the first approximation. It can be controlled by changing the ability of either G-actin or F-actin to participate in the reaction. Either of the two mechanisms alone is not sufficient to maintain a large pool of G-actin ready to polymerize in a signal-controlled fashion [1]. Mammalian cells have hundreds of actin-binding proteins (ABP) which bind either or both the forms of actin. Profilin sequesters G-actin and makes them pre-disposed towards F-actin barbed-end addition, cofilin severs F-actin and deploymerizes it into G-actin. On the other hand, capping protein (CP) caps the barbed-end and stops further elongation of F-actin [2]. Gelsolin-family of proteins [3] sever F-actin as well as cap filaments. In vitro TIRF microscopy [4] has been used to monitor real-time actin dynamics in the presence of ABPs [5], [6]. Representative results on some ABPs which alter actin assembly will be presented. [1] Pantaloni et al, Science (2001) 292: 1502-06 [2] J.A. Cooper et al, Int. Rev. Cell Mol. Biol. (2008) 267: 183-206 [3] P. Silacci et al, Cell Mol Life Sci (2004) 61: 2614-2623 [4] J.R. Kuhn et al, Biophys. J (2005) 88:1387-1402 [5] S. Nag et al, Proc. Natl. Acad. Sci. (2009) 106:13713-13718 [6] M. H.-Valladares et al, Nat Struct Mol Biol (2010) 17: 497-503

Dividing the spoils of growth and the cell cycle: The fission yeast as a model for the study of cytokinesis.

Cytokinesis is the final stage of the cell cycle, and ensures completion of both genome segregation and organelle distribution to the daughter cells. Cytokinesis requires the cell to solve a spatial problem (to divide in the correct place, orthogonally to the plane of chromosome segregation) and a temporal problem (to coordinate cytokinesis with mitosis). Defects in the spatiotemporal control of cytokinesis may cause cell death, or increase the risk of tumor formation [Fujiwara et al., 2005 (Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. 2005. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437:1043–1047); reviewed by Ganem et al., 2007 (Ganem NJ, Storchova Z, Pellman D. 2007. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 17:157–162.)]. Asymmetric cytokinesis, which permits the generation of two daughter cells that differ in their shape, size and properties, is important both during development, and for cellular homeostasis in multicellular organisms [reviewed by Li, 2007 (Li R. 2007. Cytokinesis in development and disease: variations on a common theme. Cell Mol Life Sci 64:3044–3058)]. The principal focus of this review will be the mechanisms of cytokinesis in the mitotic cycle of the yeast Schizosaccharomyces pombe. This simple model has contributed significantly to our understanding of how the cell cycle is regulated, and serves as an excellent model for studying aspects of cytokinesis. Here we will discuss the state of our knowledge of how the contractile ring is assembled and disassembled, how it contracts, and what we know of the regulatory mechanisms that control these events and assure their coordination with chromosome segregation. © 2011 Wiley-Liss, Inc.

WHERE IS THE DEIODINASE SELECTIVITY FOR ORD OR IRD LOCATED? A STRUCTURE-FUNCTION APPROACH

WHERE IS THE DEIODINASE SELECTIVITY FOR ORD OR IRD LOCATED? A STRUCTURE-FUNCTION APPROACH

Impaired Cerebral Autoregulation in Acute Mountain Sickness: Incidental Yet Adaptive?

To the Editor: Subudhi et al1 recently demonstrated that dynamic cerebral autoregulation (CA) became progressively impaired when volunteers were exposed to the hypoxia of simulated high-altitude, although this was unrelated to the onset of neurological symptoms ascribed to acute mountain sickness (AMS). Although their study describes some important findings, the authors’ interpretation of similar studies conducted by our groups2,3 warrants clarification and provides an opportunity to offer complementary insight into alternative mechanisms. The authors discuss deficiencies with the design and interpretation of our findings, thus “…making it difficult to draw conclusions regarding …

RETRACTION OF ARTICLE

To the Editor: We regret that text within our article “ The Significance of Neuroglobin in the Brain ” , published in the journal Current Medicinal Chemistry (vol. 17, pp. 160-172) was unintentionally adapted from other sources without the proper attributions to the authors who made identical interpretations from the available primary data. We deeply regret any inconvenience to the source authors for this significant oversight and wish to extend an unreserved apology to the authors, and the editorial and publishing staff of the journal. We should have directly cited the following articles as the original sources of some interpretations contained within the article in order to correctly attribute some of the concepts discussed: 1] Burmester T, Hankeln T. (2009) What is the function of neuroglobin? J Exp Biol. 212, 1423-1428. [2] Hankeln T, et al. (2005) Neuroglobin and cytoglobin in search of their role in the vertebrate globin family. J Inorg Biochem. 99, 110-119. [3] Brunori M, Vallone B. (2007) Neuroglobin, seven years after. Cell Mol Life Sci 64, 1259-1268. [4] Brunori M, Vallone B. (2006) A globin for the brain. FASEB J. 20, 2192-2197.

A novel role for sphingolipid metabolism in oxidant-mediated skeletal muscle fatigue. Focus on “Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue”

sphingolipids are a chemically diverse group of biological lipids typified by a sphingoid base backbone derived from condensation of a fatty acyl-CoA to an amino acid (typically, but not always, serine) ([24][1], [27][2]). These lipids occur throughout eukaryotic species, thus reflecting their

A cryptochrome‐based photosensory system in the siliceous sponge Suberites domuncula (Demospongiae)

Based on the light-reactive behavior of siliceous sponges, their intriguing quartz glass-based spicular system and the existence of a light-generating luciferase [Müller WEG et al. (2009) Cell Mol Life Sci 66, 537-552], a protein potentially involved in light reception has been identified, cloned and recombinantly expressed from the demosponge Suberites domuncula. Its sequence displays two domains characteristic of cryptochrome, the N-terminal photolyase-related region and the C-terminal FAD-binding domain. The expression level of S. domuncula cryptochrome depends on animal's exposure to light and is highest in tissue regions rich in siliceous spicules; in the dark, no cryptochrome transcripts/translational products are seen. From the experimental data, it is proposed that sponges might employ a luciferase-like protein, the spicular system and a cryptochrome as the light source, optical waveguide and photosensor, respectively.

Polyadenylation and degradation of incomplete RNA polymerase I transcripts in mammalian cells

Most transcripts in growing cells are ribosomal RNA precursors (pre-rRNA). Here, we show that in mammals, aberrant pre-rRNA transcripts generated by RNA polymerase I (Pol I) are polyadenylated and accumulate markedly after treatment with low concentrations of actinomycin D (ActD), which blocks the synthesis of full-length rRNA. The poly(A) polymerase-associated domain-containing protein 5 is required for polyadenylation, whereas the exosome is partly responsible for the degradation of the short aberrant transcripts. Thus, polyadenylation functions in the quality control of Pol I transcription in metazoan cells. The impact of excessive aberrant RNAs on the degradation machinery is an unrecognized mechanism that might contribute to biological properties of ActD.

104. LRGUK - A NOVEL GENE INVOLVED IN MALE FERTILITY

Infertility affects a large number of Australian men. The causative factor in many of these cases is likely to be genetic in origin. As such, the identification and characterisation of novel genes involved in male fertility represents an important area of research. We have undertaken an N-ethyl-nitrosourea (ENU) mutagenesis screen to identify novel genes involved in male fertility. From this screen we have identified a mouse line that we have designated ‘Kaos’. Male mice that are homozygous for the Kaos mutation are infertile as a result of severely disrupted spermatogenesis, with Kaos homozygote males containing only 20% of the normal number of elongated spermatids in their testes, when examined by nuclear resistance to Triton X-100 solubilisation. In contrast, Kaos homozygote females are fertile. To identify the Kaos causal mutation, we used a combination of DNA linkage analysis and candidate gene sequencing. A point mutation was identified in exon 14 of the Leucine-rich Repeats and Guanylate Kinase domain containing (Lrguk) gene, which introduces a pre-mature stop codon into the Lrguk coding sequence. The function of the LRGUK protein is currently unknown. However preliminary expression and phenotype analysis suggests that Lrguk may have a role in spermiogenesis (i.e. haploid germ cell development). The deduced LRGUK protein contains several potentially important domains including a Guanylate Kinase-like (GK) domain and a number of leucine-rich repeats. The GK-like domain has some homology to guanylate kinase, a metabolic enzyme involved in purine nucleotide metabolism. Studies are currently underway to determine whether the LRGUK protein possesses guanylate kinase enzyme activity. In other proteins, the GK-like domain has evolved into mediating protein-protein interactions (1), and current studies are also aimed at examining this possibility. These studies should provide insight into the function of LRGUK and its role in spermatogenesis. (1) Montgomery J, et al. (2004). MAGUKs in synapse assembly and function: an emerging view. Cell Mol Life Sci. 61(7–8): 911–929.

Cyclic nucleotide signaling in polycystic kidney disease

Increased levels of 3'-5'-cyclic adenosine monophosphate (cAMP) stimulate cell proliferation and fluid secretion in polycystic kidney disease. Levels of this molecule are more sensitive to inhibition of phosphodiesterases (PDEs), whose activity far exceeds the rate of cAMP synthesis by adenylyl cyclase. Several PDEs exist, and here we measured the activity and expression of PDE families, their isoforms, and the expression of downstream effectors of cAMP signaling in the kidneys of rodents with polycystic kidney disease. We found a higher overall PDE activity in kidneys from mice as compared with rats, as well as a higher contribution of PDE1, relative to PDE4 and PDE3, to total PDE activity of kidney lysates and lower PDE1, PDE3, and PDE4 activities in the kidneys of cystic as compared with wild-type mice. There were reduced amounts of several PDE1, PDE3, and PDE4 proteins, possibly due to increased protein degradation despite an upregulation of their mRNA. Increased levels of cGMP were found in the kidneys of cystic animals, suggesting in vivo downregulation of PDE1 activity. We found an additive stimulatory effect of cAMP and cGMP on cystogenesis in vitro. Cyclic AMP-dependent protein kinase subunits Ialpha and IIbeta, PKare, the transcription factor CREB-1 mRNA, and CREM, ATF-1, and ICER proteins were upregulated in the kidneys of cystic as compared with wild-type animals. Our study suggests that alterations in cyclic nucleotide catabolism may render cystic epithelium particularly susceptible to factors acting on Gs-coupled receptors. This may account, in part, for increased cyclic nucleotide signaling in polycystic kidney disease and contribute substantially to disease progression.