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Calpain Inhibition Promotes the Rescue of F508del-CFTR in PBMC from Cystic Fibrosis Patients  [PDF]
Monica Averna, Marco Pedrazzi, Laura Minicucci, Roberta De Tullio, Federico Cresta, Franca Salamino, Sandro Pontremoli, Edon Melloni
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066089
Abstract: A basal calpain activity promotes the limited proteolysis of wild type (WT) cystic fibrosis conductance regulator (CFTR), inducing the internalization of the split channel. This process contributes to the regulation in the level of the active CFTR at the plasma membranes. In peripheral blood mononuclear cells (PBMC) from 16 healthy donors, the inhibition of calpain activity induces a 3-fold increase in the amount of active WT CFTR at the plasma membranes. Instead, in PBMC from cystic fibrosis (CF) patients, calpain activity is expressed at aberrant levels causing the massive removal of F508del-CFTR from the cell surface. In these patients, the inhibition of such abnormal proteolysis rescues physiological amounts of active mutated CFTR in 90% of the patients (25 over 28). The recovery of functional F508del-CFTR at the physiological location, in cells treated with a synthetic calpain inhibitor, indicates that F508del-CFTR folding, maturation, and trafficking operate in CF-PBMC at significant rate. Thus, an increase in the basal calpain activity seems primarily involved in the CFTR defect observed in various CF cells. Furthermore, in CF-PBMC the recovery of the scaffolding protein Na+/H+ exchanger regulatory factor 1 (NHERF-1), occurring following inhibition of the aberrant calpain activity, can contribute to rescue CFTR-functional clusters.
Ego-Depletion Promotes Altruistic Punishment  [PDF]
Yaozhong Liu, Na He, Kai Dou
Open Journal of Social Sciences (JSS) , 2015, DOI: 10.4236/jss.2015.311009
Abstract: To explore whether psychological resource influences the altruistic punishment, Experiment 1 used the Stroop Task to manipulate participants’ self-control resources and the rejection ratio of unfair proposals in the subsequent Ultimate Game was measured to reveal the effect of self-depletion on altruistic punishment. The result of Experiment 1 showed that decline ratio of participants in the high-depletion group was significantly higher than that of participants in the low-depletion group. After manipulation of self-depletion with the Stroop task, participants in experiment 2 acted as the third-party who watched other two participants playing the Dictator Game and could use their own tokens to punish unfair proposals. The result of Experiment 2 showed that participants in the high-depletion group punished unfair proposals significantly more than counterparts in the low-depletion group. In sum, the results of these two experiments showed that ego depletion promoted altruistic punishment.
Lipoxin A4 and Platelet Activating Factor Are Involved in E. coli or LPS-Induced Lung Inflammation in CFTR-Deficient Mice  [PDF]
Haiya Wu, Jun Yang, Emily M. Su, Ling Li, Caiqi Zhao, Xi Yang, Zhaowei Gao, Mengyao Pan, Peiyu Sun, Wei Sun, Yiyi Jiang, Xiao Su
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093003
Abstract: CFTR (cystic fibrosis transmembrane conductance regulator) is expressed by both neutrophils and platelets. Lack of functional CFTR could lead to severe lung infection and inflammation. Here, we found that mutation of CFTR (F508del) or inhibition of CFTR in mice led to more severe thrombocytopenia, alveolar neutrocytosis and bacteriosis, and lower lipoxin A4/MIP-2 (macrophage inhibitory protein-2) or lipoxin A4/neutrophil ratios in the BAL (bronchoalveolar lavage) during acute E. coli pneumonia. In vitro, inhibition of CFTR promotes MIP-2 production in LPS-stimulated neutrophils; however, lipoxin A4 could dose-dependently suppress this effect. In LPS-induced acute lung inflammation, blockade of PSGL-1 (P-selectin glycoprotein ligand-1) or P-selectin, antagonism of PAF by WEB2086, or correction of mutated CFTR trafficking by KM11060 could significantly increase plasma lipoxin A4 levels in F508del relevant to wildtype mice. Concurrently, F508del mice had higher plasma platelet activating factor (PAF) levels and PAF-AH activity compared to wildtype under LPS challenge. Inhibiting hydrolysis of PAF by a specific PAF-AH (PAF-acetylhydrolase) inhibitor, MAFP, could worsen LPS-induced lung inflammation in F508del mice compared to vehicle treated F508del group. Particularly, depletion of platelets in F508del mice could significantly decrease plasma lipoxin A4 and PAF-AH activity and deteriorate LPS-induced lung inflammation compared to control F508del mice. Taken together, lipoxin A4 and PAF are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice, suggesting that lipoxin A4 and PAF might be therapeutic targets for ameliorating CFTR-deficiency deteriorated lung inflammation.
Depletion of T-cell intracellular antigen proteins promotes cell proliferation
Raquel Reyes, José Alcalde, José M Izquierdo
Genome Biology , 2009, DOI: 10.1186/gb-2009-10-8-r87
Abstract: Using high-throughput gene expression profiling, we found that the TIA-1/TIAR-depleted cell phenotype is linked to a transcriptome involved in the control of inflammation, cell-cell signaling, immune-suppression, angiogenesis, metabolism and cell proliferation. Induced genes included pro-inflammatory cytokines, inflammatory chemokines, growth-stimulating factors and pro-angiogenic inducers. Repressed genes involved the RAS oncogene family member RAB40B, regulators of cytoskeleton organization and biogenesis and a mitochondrial modulator. Consistent with these observations, depletion of TIA proteins in HeLa cells results in increased cell proliferation, altered cell-cycle and anchorage-independent growth. Mechanistically, the changes associated with the steady-state target mRNA levels regulated by TIA proteins are consistent with overlapping effects on gene basal transcription rate and mRNA turnover.Collectively, our findings suggest a role for TIA proteins as cellular sensors that modulate gene expression control at the transcriptional and post-transcriptional levels, coupling cell proliferation responses and metabolic homeostasis to cell survival and growth.One of the most important challenges resulting from our knowledge of the human genome - and, in general, of all genomes - is to understand how the collection of RNAs and proteins that define us as an organism are generated. Nowadays, we accept that the origin of our transcriptomic and proteomic diversity is due not just to the number of genes present in our genome but also to the dynamic and differential regulation of their expression. The characterization of transcriptional and post-transcriptional events leading to the generation of multiple RNAs, proteins and functions from a single or distinct RNA precursors reveals the existence of multiple layers and networks involved in regulating the diverse biological functions controlled by the transcriptome [1].T-cell intracellular antigen (TIA)-1 and TIA-1 related/li
Hepatic n-3 Polyunsaturated Fatty Acid Depletion Promotes Steatosis and Insulin Resistance in Mice: Genomic Analysis of Cellular Targets  [PDF]
Barbara D. Pachikian, Ahmed Essaghir, Jean-Baptiste Demoulin, Audrey M. Neyrinck, Emilie Catry, Fabienne C. De Backer, Nicolas Dejeans, Evelyne M. Dewulf, Florence M. Sohet, Laurence Portois, Louise Deldicque, Olivier Molendi-Coste, Isabelle A. Leclercq, Marc Francaux, Yvon A. Carpentier, Fabienne Foufelle, Giulio G. Muccioli, Patrice D. Cani, Nathalie M. Delzenne
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023365
Abstract: Patients with non-alcoholic fatty liver disease are characterised by a decreased n-3/n-6 polyunsaturated fatty acid (PUFA) ratio in hepatic phospholipids. The metabolic consequences of n-3 PUFA depletion in the liver are poorly understood. We have reproduced a drastic drop in n-3 PUFA among hepatic phospholipids by feeding C57Bl/6J mice for 3 months with an n-3 PUFA depleted diet (DEF) versus a control diet (CT), which only differed in the PUFA content. DEF mice exhibited hepatic insulin resistance (assessed by euglycemic-hyperinsulinemic clamp) and steatosis that was associated with a decrease in fatty acid oxidation and occurred despite a higher capacity for triglyceride secretion. Microarray and qPCR analysis of the liver tissue revealed higher expression of all the enzymes involved in lipogenesis in DEF mice compared to CT mice, as well as increased expression and activation of sterol regulatory element binding protein-1c (SREBP-1c). Our data suggest that the activation of the liver X receptor pathway is involved in the overexpression of SREBP-1c, and this phenomenon cannot be attributed to insulin or to endoplasmic reticulum stress responses. In conclusion, n-3 PUFA depletion in liver phospholipids leads to activation of SREBP-1c and lipogenesis, which contributes to hepatic steatosis.
COMMD1-Mediated Ubiquitination Regulates CFTR Trafficking  [PDF]
Lo?c Drévillon,Ga?lle Tanguy,Alexandre Hinzpeter,Nicole Arous,Alix de Becdelièvre,Abdel Aissat,Agathe Tarze,Michel Goossens,Pascale Fanen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018334
Abstract: The CFTR (cystic fibrosis transmembrane conductance regulator) protein is a large polytopic protein whose biogenesis is inefficient. To better understand the regulation of CFTR processing and trafficking, we conducted a genetic screen that identified COMMD1 as a new CFTR partner. COMMD1 is a protein associated with multiple cellular pathways, including the regulation of hepatic copper excretion, sodium uptake through interaction with ENaC (epithelial sodium channel) and NF-kappaB signaling. In this study, we show that COMMD1 interacts with CFTR in cells expressing both proteins endogenously. This interaction promotes CFTR cell surface expression as assessed by biotinylation experiments in heterologously expressing cells through regulation of CFTR ubiquitination. In summary, our data demonstrate that CFTR is protected from ubiquitination by COMMD1, which sustains CFTR expression at the plasma membrane. Thus, increasing COMMD1 expression may provide an approach to simultaneously inhibit ENaC absorption and enhance CFTR trafficking, two major issues in cystic fibrosis.
Defective CFTR-Dependent CREB Activation Results in Impaired Spermatogenesis and Azoospermia  [PDF]
Wen Ming Xu,Jing Chen,Hui Chen,Rui Ying Diao,Kin Lam Fok,Jian Da Dong,Ting Ting Sun,Wen Ying Chen,Mei Kuen Yu,Xiao Hu Zhang,Lai Ling Tsang,Ann Lau,Qi Xian Shi,Qing Hua Shi,Ping Bo Huang,Hsiao Chang Chan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019120
Abstract: Cystic fibrosis (CF) is the most common life-limiting recessive genetic disease among Caucasians caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) with over 95% male patients infertile. However, whether CFTR mutations could affect spermatogenesis and result in azoospermia remains an open question. Here we report compromised spermatogenesis, with significantly reduced testicular weight and sperm count, and decreased cAMP-responsive element binding protein (CREB) expression in the testes of CFTR knockout mice. The involvement of CFTR in HCO3? transport and the expression of the HCO3? sensor, soluble adenylyl cyclase (sAC), are demonstrated for the first time in the primary culture of rat Sertoli cells. Inhibition of CFTR or depletion of HCO3? could reduce FSH-stimulated, sAC-dependent cAMP production and phosphorylation of CREB, the key transcription factor in spermatogenesis. Decreased CFTR and CREB expression are also observed in human testes with azoospermia. The present study reveals a previously undefined role of CFTR and sAC in regulating the cAMP-CREB signaling pathway in Sertoli cells, defect of which may result in impaired spermatogenesis and azoospermia. Altered CFTR-sAC-cAMP-CREB functional loop may also underline the pathogenesis of various CF-related diseases.
Depletion of Retinoic Acid Receptors Initiates a Novel Positive Feedback Mechanism that Promotes Teratogenic Increases in Retinoic Acid  [PDF]
Enrico D'Aniello,Ariel B. Rydeen,Jane L. Anderson,Amrita Mandal,Joshua S. Waxman
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003689
Abstract: Normal embryonic development and tissue homeostasis require precise levels of retinoic acid (RA) signaling. Despite the importance of appropriate embryonic RA signaling levels, the mechanisms underlying congenital defects due to perturbations of RA signaling are not completely understood. Here, we report that zebrafish embryos deficient for RA receptor αb1 (RARαb1), a conserved RAR splice variant, have enlarged hearts with increased cardiomyocyte (CM) specification, which are surprisingly the consequence of increased RA signaling. Importantly, depletion of RARαb2 or concurrent depletion of RARαb1 and RARαb2 also results in increased RA signaling, suggesting this effect is a broader consequence of RAR depletion. Concurrent depletion of RARαb1 and Cyp26a1, an enzyme that facilitates degradation of RA, and employment of a novel transgenic RA sensor line support the hypothesis that the increases in RA signaling in RAR deficient embryos are the result of increased embryonic RA coupled with compensatory RAR expression. Our results support an intriguing novel mechanism by which depletion of RARs elicits a previously unrecognized positive feedback loop that can result in developmental defects due to teratogenic increases in embryonic RA.
Depletion of Cutaneous Macrophages and Dendritic Cells Promotes Growth of Basal Cell Carcinoma in Mice  [PDF]
Simone K?nig, Frauke Nitzki, Anja Uhmann, Kai Dittmann, Jennifer Theiss-Suennemann, Markus Herrmann, Holger M. Reichardt, Reto Schwendener, Tobias Pukrop, Walter Schulz-Schaeffer, Heidi Hahn
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093555
Abstract: Basal cell carcinoma (BCC) belongs to the group of non-melanoma skin tumors and is the most common tumor in the western world. BCC arises due to mutations in the tumor suppressor gene Patched1 (Ptch). Analysis of the conditional Ptch knockout mouse model for BCC reveals that macrophages and dendritic cells (DC) of the skin play an important role in BCC growth restraining processes. This is based on the observation that a clodronate-liposome mediated depletion of these cells in the tumor-bearing skin results in significant BCC enlargement. The depletion of these cells does not modulate Ki67 or K10 expression, but is accompanied by a decrease in collagen-producing cells in the tumor stroma. Together, the data suggest that cutaneous macrophages and DC in the tumor microenvironment exert an antitumor effect on BCC.
Depletion of the Adaptor Protein NCK Increases UV-Induced p53 Phosphorylation and Promotes Apoptosis  [PDF]
Timothy M. Errington, Ian G. Macara
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076204
Abstract: The cellular response to DNA damage requires the coordination of many proteins involved in diverse molecular processes. Discrete molecular pathways are becoming increasingly well understood, but the interconnectivity and coordination of multiple pathways remains less clear. We now show that NCK, an adapter protein involved in cytoskeletal responses to tyrosine kinase receptor signaling, accumulates in the nucleus in response to DNA damage and this translocation can be blocked by specific inhibition of the ATR protein kinase. Strikingly, HeLa cells depleted of NCK undergo apoptosis shortly after UV irradiation, as monitored by caspase-3 cleavage and PARP cleavage. This rapid, hyperactive apoptosis in NCK depleted cells might be p53 dependent, because loss of NCK also increased UV-induced p53 phosphorylation. Importantly, depletion of SOCS7, which is necessary for NCK nuclear translocation, phenocopies NCK depletion, indicating the nuclear accumulation of NCK is responsible for these molecular events. There are two NCK isoforms that have mostly redundant functions, and although NCK2 appears to have a greater contribution, depletion of NCK1 or NCK2, led to increased p53 phosphorylation and early apoptosis after UV exposure. These data reveal a novel function for NCK in regulating p53 phosphorylation and apoptosis, and provide evidence for interconnectedness of growth factor signaling proteins and the DNA damage response.
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