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133.
Cell signaling systems transmit information by post-translationally modifying signaling proteins, often via phosphorylation. While thousands of sites of phosphorylation have been identified in proteomic studies, the vast majority of sites have no known function. Assigning functional roles to the catalog of uncharacterized phosphorylation sites is a key research challenge. Here we present a general approach to address this challenge and apply it to a prototypical signaling pathway, the pheromone response pathway in Saccharomyces cerevisiae. The pheromone pathway includes a mitogen activated protein kinase (MAPK) cascade activated by a G-protein coupled receptor (GPCR). We used published mass spectrometry-based proteomics data to identify putative sites of phosphorylation on pheromone pathway components, and we used evolutionary conservation to assign priority to a list of candidate MAPK regulatory sites. We made targeted alterations in those sites, and measured the effects of the mutations on pheromone pathway output in single cells. Our work identified six new sites that quantitatively tuned system output. We developed simple computational models to find system architectures that recapitulated the quantitative phenotypes of the mutants. Our results identify a number of putative phosphorylation events that contribute to adjust the input-output relationship of this model eukaryotic signaling system. We believe this combined approach constitutes a general means not only to reveal modification sites required to turn a pathway on and off, but also those required for more subtle quantitative effects that tune pathway output. Our results suggest that relatively small quantitative influences from individual phosphorylation events endow signaling systems with plasticity that evolution may exploit to quantitatively tailor signaling outcomes. 相似文献
134.
Hila Gingold Disa Tehler Nanna R. Christoffersen Morten M. Nielsen Fazila Asmar Susanne M. Kooistra Nicolaj S. Christophersen Lise Lotte Christensen Michael Borre Karina D. Sørensen Lars D. Andersen Claus L. Andersen Esther Hulleman Tom Wurdinger Elisabeth Ralfkiær Kristian Helin Kirsten Grønbæk Torben Ørntoft Sebastian M. Waszak Orna Dahan Jakob Skou Pedersen Anders H. Lund Yitzhak Pilpel 《Cell》2014
135.
136.
Meghan E. Fitzpatrick John R. Tedrow Maria E. Hillenbrand Lorrie Lucht Thomas Richards Karen A. Norris Yingze Zhang Frank C. Sciurba Naftali Kaminski Alison Morris 《Microbiology and immunology》2014,58(3):202-211
Chronic obstructive pulmonary disease (COPD) is a complex disease, the pathogenesis of which remains incompletely understood. Colonization with Pneumocystis jirovecii may play a role in COPD pathogenesis; however, the mechanisms by which such colonization contributes to COPD are unknown. The objective of this study was to determine lung gene expression profiles associated with Pneumocystis colonization in patients with COPD to identify potential key pathways involved in disease pathogenesis. Using COPD lung tissue samples made available through the Lung Tissue Research Consortium (LTRC), Pneumocystis colonization status was determined by nested PCR. Microarray gene expression profiles were performed for each sample and the profiles of colonized and non‐colonized samples compared. Overall, 18 participants (8.5%) were Pneumocystis‐colonized. Pneumocystis colonization was associated with fold increase in expression of four closely related genes: INF‐γ and the three chemokine ligands CXCL9, CXCL10, and CXCL11. These ligands are chemoattractants for the common cognate receptor CXCR3, which is predominantly expressed on activated Th1 T‐lymphocytes. Although these ligand–receptor pairs have previously been implicated in COPD pathogenesis, few initiators of ligand expression and subsequent lymphocyte trafficking have been identified: our findings implicate Pneumocystis as a potential trigger. The finding of upregulation of these inflammatory genes in the setting of Pneumocystis colonization sheds light on infectious‐immune relationships in COPD. 相似文献
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139.
Corrine R. Kliment Judson M. Englert Bernadette R. Gochuico Guoying Yu Naftali Kaminski Ivan Rosas Tim D. Oury 《The Journal of biological chemistry》2009,284(6):3537-3545
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease
characterized by severe, progressive fibrosis. Roles for inflammation and
oxidative stress have recently been demonstrated, but despite advances in
understanding the pathogenesis, there are still no effective therapies for
IPF. This study investigates how extracellular superoxide dismutase (EC-SOD),
a syndecan-binding antioxidant enzyme, inhibits inflammation and lung
fibrosis. We hypothesize that EC-SOD protects the lung from oxidant damage by
preventing syndecan fragmentation/shedding. Wild-type or EC-SOD-null mice were
exposed to an intratracheal instillation of asbestos or bleomycin. Western
blot was used to detect syndecans in the bronchoalveolar lavage fluid and
lung. Human lung samples (normal and IPF) were also analyzed.
Immunohistochemistry for syndecan-1 and EC-SOD was performed on human and
mouse lungs. In vitro, alveolar epithelial cells were exposed to
oxidative stress and EC-SOD. Cell supernatants were analyzed for shed
syndecan-1 by Western blot. Syndecan-1 ectodomain was assessed in wound
healing and neutrophil chemotaxis. Increases in human syndecan-1 are detected
in lung homogenates and lavage fluid of IPF lungs. Syndecan-1 is also
significantly elevated in the lavage fluid of EC-SOD-null mice after asbestos
and bleomycin exposure. On IHC, syndecan-1 staining increases within fibrotic
areas of human and mouse lungs. In vitro, EC-SOD inhibits
oxidant-induced loss of syndecan-1 from A549 cells. Shed and exogenous
syndecan-1 ectodomain induce neutrophil chemotaxis, inhibit alveolar
epithelial wound healing, and promote fibrogenesis. Oxidative shedding of
syndecan-1 is an underlying cause of neutrophil chemotaxis and aberrant wound
healing that may contribute to pulmonary fibrosis.Idiopathic pulmonary fibrosis
(IPF)2 is an
interstitial lung disease characterized by severe and progressive fibrosis.
IPF patients have a mean survival of 3–5 years
(1,
2) and no effective therapies
(3,
4), other than orthotopic lung
transplantation, have proven to improve survival. The pathogenesis of IPF is
poorly understood; however, inflammation and oxidant/antioxidant imbalances in
the lung are thought to play important roles
(5–7).
A better understanding of the molecular mechanisms involved in oxidative
injury and fibrosis could lead to the development of novel therapeutic
targets.Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme bound
to heparan sulfate in the lung extracellular matrix
(8–10),
which can inhibit inflammation
(11,
12) and prevent subsequent
development of fibrosis
(13–16).
Despite its beneficial role, the mechanisms through which EC-SOD protects the
lung remain unknown.The extracellular matrix (ECM) is essential for tissue homeostasis and
changes in the ECM microenvironment can be detrimental to cell function during
inflammation and wound healing. Heparan sulfate proteoglycans (HSPG) contain a
membrane-bound core protein and extracellular carbohydrate side chains.
Syndecans are the most abundant HSPG in humans; there are 4 isoforms with
variable cell expression (17,
18). Both syndecan-1 and -4
are expressed in the lung, with epithelial cell and ubiquitous expression,
respectively (19). Syndecans
are essential for ECM homeostasis by binding cytokines and growth factors,
acting as co-receptors and soluble effectors. They also have potential roles
in inflammation (18,
20,
21), fibrosis
(22,
23), and wound healing
(24–26).
Syndecans are shed under physiological and pathological conditions but the
function of shed syndecans is poorly understood
(22). Reactive oxygen species
(ROS) are capable of fragmenting HSPG
(27) and other ECM components.
Notably, EC-SOD has been shown to prevent oxidative damage to many ECM
components (23,
28,
29). Within the lung, EC-SOD
binds to syndecan-1 on the cell surface via a heparin-binding domain
(8,
30). Because of the known
functions of syndecans and its close interaction with EC-SOD, syndecan-1 is a
key target that may contribute to the anti-inflammatory and anti-fibrotic
effects of EC-SOD in the lung and in the pulmonary fibrosis.This study was conducted to determine the role of EC-SOD in protecting the
ECM from oxidative stress and to investigate our hypothesis that EC-SOD
protects the lung from inflammation and fibrosis by inhibiting oxidant-induced
shedding of syndecan-1. Our findings suggest that a loss of EC-SOD in the lung
leaves syndecan-1 vulnerable to oxidative stress and that oxidatively shed
syndecan-1 ectodomain induces neutrophil chemotaxis, impairs epithelial wound
healing, and promotes fibrogenesis. The discovery that oxidative stress alters
the distribution of syndecan-1 in the lung microenvironment is a novel finding
in the context of pulmonary fibrosis. These findings advance the understanding
of the pathogenesis of idiopathic pulmonary fibrosis and provide a potential
new therapeutic target for intervention in IPF. 相似文献
140.
Pappo O Ben-Ari Z Shevtsov E Avlas O Gassmann M Ravid A Cheporko Y Hochhauser E 《Canadian journal of physiology and pharmacology》2010,88(12):1130-1137
Ischemia-reperfusion injury (I/R) is the main cause of primary graft nonfunction. Our aim was to evaluate the effect of excessive versus acute administration of erythropoietin (EPO) in attenuating the hepatic injury induced by I/R in mice. The effect of segmental (70%) hepatic ischemia was evaluated in a transgenic mouse line with constitutive overexpression of human EPO cDNA and in wild-type (WT) mice. Mice were randomly allocated to 5 main experimental groups: (i) WT-sham, (ii) WT ischemia, (iii) WT ischemia + recombinant human erythropoietin (rhEPO), (iv) transgenic-sham, and (v) transgenic ischemia. The EPO-pretreated mice showed a significant reduction in liver enzyme levels and intrahepatic caspase-3 activity and fewer apoptotic hepatocytes (p < 0.05 for all) compared with the WT untreated I/R group. EPO decreased c-Jun N-terminal kinase (JNK) phosphorylation and nuclear factor-κB (NF-κB) expression during I/R. In transgenic I/R livers, baseline histology showed diffused hepatic injury, and no significant beneficial effect was noted between the WT untreated and the transgenic I/R mice. In conclusion, acute pretreatment with EPO in WT mice attenuated in vivo I/R liver injury. However, in excessive EPO overexpression, the initial liver injury abolished the beneficial effect of EPO. These findings have important implications for the potential use of acute EPO in I/R injury during liver transplantation. 相似文献