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MFSD2A is a novel lung tumor suppressor gene modulating cell cycle and matrix attachment
Monica Spinola, Felicia S Falvella, Francesca Colombo, James P Sullivan, David S Shames, Luc Girard, Paola Spessotto, John D Minna, Tommaso A Dragani
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-62
Abstract: Here we show that MFSD2A expression is strongly downregulated in non-small cell lung cancer cell lines of different histotypes and in primary lung adenocarcinomas. Experimental modulation of MFSD2A in lung cancer cells is associated with alteration of mRNA levels of genes involved in cell cycle control and interaction with the extracellular matrix. Exogenous expression of MFSD2A in lung cancer cells induced a G1 block, impaired adhesion and migration in vitro, and significantly reduced tumor colony number in vitro (4- to 27-fold, P < 0.0001) and tumor volume in vivo (~3-fold, P < 0.0001). siRNA knockdown studies in normal human bronchial epithelial cells confirmed the role of MFSD2A in G1 regulation.Together these data suggest that MFSD2A is a novel lung cancer tumor suppressor gene that regulates cell cycle progression and matrix attachment.Cancer progression is defined as the stepwise process through which cells evolve towards a more malignant and aggressive phenotype [1]. This process results from the accumulation of somatic genetic and epigenetic changes occurring within neoplastic cells [2]. However, a growing body of evidence also points to the role of genetic background in cancer susceptibility, progression, and prognosis [3-5]. We previously identified a 106 kb linkage disequilibrium block containing genetic elements associated with survival in lung adenocarcinoma (ADCA) patients [6]. The refined region maps to chromosome 1p34 and includes MYCL1, TRIT1 (tRNA isopentenyltransferase 1), and MFSD2A (major facilitator superfamily domain containing 2). While the role of MYCL1 and TRIT1 in lung tumor growth and development has been studied [6,7], no information is available on MFSD2A. Thus, we addressed the functional role of MFSD2A in lung tumorigenesis.Based on our previous finding of MFSD2A downregulation in a pool of lung tumor specimens [7], we extended the analysis to 18 individual samples of lung ADCA tumors and corresponding benign adjacent tissue. MFSD2A
Modulation of Bacterial Multidrug Resistance Efflux Pumps of the Major Facilitator Superfamily  [PDF]
Sanath Kumar,Mun Mun Mukherjee,Manuel F. Varela
International Journal of Bacteriology , 2013, DOI: 10.1155/2013/204141
Abstract: Bacterial infections pose a serious public health concern, especially when an infectious disease has a multidrug resistant causative agent. Such multidrug resistant bacteria can compromise the clinical utility of major chemotherapeutic antimicrobial agents. Drug and multidrug resistant bacteria harbor several distinct molecular mechanisms for resistance. Bacterial antimicrobial agent efflux pumps represent a major mechanism of clinical resistance. The major facilitator superfamily (MFS) is one of the largest groups of solute transporters to date and includes a significant number of bacterial drug and multidrug efflux pumps. We review recent work on the modulation of multidrug efflux pumps, paying special attention to those transporters belonging primarily to the MFS. 1. Introduction Drug and multidrug resistant bacterial pathogens that are causative agents of infectious disease constitute a serious public health concern. Bacterial multidrug efflux pump systems of the major facilitator superfamily (MFS) and resistance-nodulation-cell division (RND) superfamily represent common mechanisms for bacterial resistance to antimicrobial agents. As such these bacterial transporters make suitable targets for modulation in order to restore the clinical efficacy of relevant chemotherapeutic antibacterial agents. Here, we briefly review the drug transporter systems of the MFS (and to a lesser extent the RND superfamily) and discuss their modulation via regulation of expression and efflux pump transport inhibition. 2. Bacteria and Pathogenesis Bacteria are unicellular, microscopic living organisms that are rod shaped, ball shaped, or spiral shaped when observed under the microscope. Most bacteria are not harmful; rather, they aid in food preparation and digestion, compete with pathogens, provide vitamins to the body, are useful for basic and applied research purposes, and are important in biotechnology. However, less than one percent of the bacteria of different types are responsible for causing bacterial infections. Bacterial cells are capable of quickly reproducing and releasing chemicals and toxins; pathogenic bacteria can cause damage to cells and tissues in the body and cause clinical disease. Some of the common diseases and infections caused by pathogenic strains of bacteria include food poisoning caused by Escherichia coli and Salmonella [1–6], gastritis and ulcers caused by Helicobacter pylori [7], the sexually transmitted disease gonorrhea caused by Neisseria gonorrhoeae [8], meningitis caused by N. meningitides [9], skin infections like boils, cellulitis,
Roles of Major Facilitator Superfamily Transporters in Phosphate Response in Drosophila  [PDF]
Clemens Bergwitz, Matthew D. Rasmussen, Charles DeRobertis, Mark J. Wee, Sumi Sinha, Hway H. Chen, Joanne Huang, Norbert Perrimon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031730
Abstract: The major facilitator superfamily (MFS) transporter Pho84 and the type III transporter Pho89 are responsible for metabolic effects of inorganic phosphate in yeast. While the Pho89 ortholog Pit1 was also shown to be involved in phosphate-activated MAPK in mammalian cells, it is currently unknown, whether orthologs of Pho84 have a role in phosphate-sensing in metazoan species. We show here that the activation of MAPK by phosphate observed in mammals is conserved in Drosophila cells, and used this assay to characterize the roles of putative phosphate transporters. Surprisingly, while we found that RNAi-mediated knockdown of the fly Pho89 ortholog dPit had little effect on the activation of MAPK in Drosophila S2R+ cells by phosphate, two Pho84/SLC17A1–9 MFS orthologs (MFS10 and MFS13) specifically inhibited this response. Further, using a Xenopus oocyte assay, we show that MSF13 mediates uptake of [33P]-orthophosphate in a sodium-dependent fashion. Consistent with a role in phosphate physiology, MSF13 is expressed highest in the Drosophila crop, midgut, Malpighian tubule, and hindgut. Altogether, our findings provide the first evidence that Pho84 orthologs mediate cellular effects of phosphate in metazoan cells. Finally, while phosphate is essential for Drosophila larval development, loss of MFS13 activity is compatible with viability indicating redundancy at the levels of the transporters.
Function, Structure, and Evolution of the Major Facilitator Superfamily: The LacY Manifesto  [PDF]
M. Gregor Madej
Advances in Biology , 2014, DOI: 10.1155/2014/523591
Abstract: The major facilitator superfamily (MFS) is a diverse group of secondary transporters with members found in all kingdoms of life. A paradigm for MFS is the lactose permease (LacY) of Escherichia coli, which couples the stoichiometric translocation of a galactopyranoside and an across the cytoplasmic membrane. LacY has been the test bed for the development of many methods applied for the analysis of transport proteins. X-ray structures of an inward-facing conformation and the most recent structure of an almost occluded conformation confirm many conclusions from previous studies. Although structure models are critical, they are insufficient to explain the catalysis of transport. The clues to understanding transport are based on the principles of enzyme kinetics. Secondary transport is a dynamic process—static snapshots of X-ray crystallography describe it only partially. However, without structural information, the underlying chemistry is virtually impossible to conclude. A large body of biochemical/biophysical data derived from systematic studies of site-directed mutants in LacY suggests residues critically involved in the catalysis, and a working model for the symport mechanism that involves alternating access of the binding site is presented. The general concepts derived from the bacterial LacY are examined for their relevance to other MFS transporters. 1. Introduction Proteins can act as molecular devices to convert one energy form to another through cycles of conformational transitions. Symporters, antiporters, transporters, carriers, or permeases are such molecular devices that catalyze substrate-specific equilibration and/or translocation of solutes across a biological membrane (Figure 1(a)). In 1955, when the existence of cell membranes themselves was still being questioned, let alone the existence of proteins that transport solutes specifically across them, Cohen and Rickenberg [1] found an inducible transport system for lactose in Escherichia coli, and it was subsequently found to be part of the famous lac operon [2]. This discovery was the first time that a transport function was associated with genetics and indicated that a protein might be involved. Figure 1: Transport reactions catalyzed by MFS. (a) Schematic illustration of active transports (symport, e.g., LacY, and antiport, e.g., GlpT) and facilitated diffusion (e.g., GLUT1). The red and green arrows indicate the transport directions of substrate and cosubstrate. (b) Uphill substrate (S) accumulation in response to generated by either respiration or ATP hydrolysis by F 1F O-ATPase. (c)
Integration of Evolutionary Features for the Identification of Functionally Important Residues in Major Facilitator Superfamily Transporters  [PDF]
Jouhyun Jeon,Jae-Seong Yang,Sanguk Kim
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000522
Abstract: The identification of functionally important residues is an important challenge for understanding the molecular mechanisms of proteins. Membrane protein transporters operate two-state allosteric conformational changes using functionally important cooperative residues that mediate long-range communication from the substrate binding site to the translocation pathway. In this study, we identified functionally important cooperative residues of membrane protein transporters by integrating sequence conservation and co-evolutionary information. A newly derived evolutionary feature, the co-evolutionary coupling number, was introduced to measure the connectivity of co-evolving residue pairs and was integrated with the sequence conservation score. We tested this method on three Major Facilitator Superfamily (MFS) transporters, LacY, GlpT, and EmrD. MFS transporters are an important family of membrane protein transporters, which utilize diverse substrates, catalyze different modes of transport using unique combinations of functional residues, and have enough characterized functional residues to validate the performance of our method. We found that the conserved cores of evolutionarily coupled residues are involved in specific substrate recognition and translocation of MFS transporters. Furthermore, a subset of the residues forms an interaction network connecting functional sites in the protein structure. We also confirmed that our method is effective on other membrane protein transporters. Our results provide insight into the location of functional residues important for the molecular mechanisms of membrane protein transporters.
Basic Residues R260 and K357 Affect the Conformational Dynamics of the Major Facilitator Superfamily Multidrug Transporter LmrP  [PDF]
Wei Wang, Hendrik W. van Veen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038715
Abstract: Secondary-active multidrug transporters can confer resistance on cells to pharmaceuticals by mediating their extrusion away from intracellular targets via substrate/H+(Na+) antiport. While the interactions of catalytic carboxylates in these transporters with coupling ions and substrates (drugs) have been studied in some detail, the functional importance of basic residues has received much less attention. The only two basic residues R260 and K357 in transmembrane helices in the Major Facilitator Superfamily transporter LmrP from Lactococcus lactis are present on the outer surface of the protein, where they are exposed to the phospholipid head group region of the outer leaflet (R260) and inner leaflet (K357) of the cytoplasmic membrane. Although our observations on the proton-motive force dependence and kinetics of substrate transport, and substrate-dependent proton transport demonstrate that K357A and R260A mutants are affected in ethidium-proton and benzalkonium-proton antiport compared to wildtype LmrP, our findings suggest that R260 and K357 are not directly involved in the binding of substrates or the translocation of protons. Secondary-active multidrug transporters are thought to operate by a mechanism in which binding sites for substrates are alternately exposed to each face of the membrane. Disulfide crosslinking experiments were performed with a double cysteine mutant of LmrP that reports the substrate-stimulated transition from the outward-facing state to the inward-facing state with high substrate-binding affinity. In the experiments, the R260A and K357A mutations were found to influence the dynamics of these major protein conformations in the transport cycle, potentially by removing the interactions of R260 and K357 with phospholipids and/or other residues in LmrP. The R260A and K357A mutations therefore modify the maximum rate at which the transport cycle can operate and, as the transitions between conformational states are differently affected by components of the proton-motive force, the mutations also influence the energetics of transport.
Selaginella moellendorffii has a reduced and highly conserved expansin superfamily with genes more closely related to angiosperms than to bryophytes
Robert E Carey, Nathan K Hepler, Daniel J Cosgrove
BMC Plant Biology , 2013, DOI: 10.1186/1471-2229-13-4
Abstract: The expansin superfamily in Selaginella moellendorffii has now been assembled from genomic scaffolds. A smaller (and less diverse) superfamily is revealed, consistent with studies of other gene families in Selaginella. Selaginella has an expansin superfamily, which, like Physcomitrella, lacks EXLA or EXLB genes, but does contain two EXPA genes that are related to a particular Arabidopsis-rice clade involved in root hair development.From sequence-based phylogenetic analysis, most Selaginella expansins lie outside the Arabidopsis-rice clades, leading us to estimate the minimum number of expansins present in the last common ancestor of Selaginella and angiosperms at 2 EXPA genes and 1 EXPB gene. These results confirm Selaginella as an important intermediary between bryophytes and angiosperms.
A 5'-region polymorphism modulates promoter activity of the tumor suppressor gene MFSD2A
Francesca Colombo, Felicia S Falvella, Antonella Galvan, Elisa Frullanti, Hideo Kunitoh, Toshikazu Ushijima, Tommaso A Dragani
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-81
Abstract: Analysis of three single-nucleotide polymorphisms (SNPs) mapping in the MFSD2A 5'-regulatory region using a luciferase reporter system showed that SNP rs12072037, in linkage disequilibrium with the MYCL1-EcoRI polymorphism and polymorphic in Asians but not in Caucasians, modulated transcriptional activity of the MFSD2A promoter in cell lines expressing AHR and ARNT transcription factors, which potentially bind to the SNP site.SNP rs12072037 modulates MFSD2A promoter activity and thus might affect MFSD2A levels in normal lung and in lung tumors, representing a candidate ethnically specific genetic factor underlying the association between the MYCL1 locus and lung cancer patients' survival.A 106-kb linkage disequilibrium (LD) block on chromosome 1p34, which includes the TRIT1, MYCL1, and MFSD2A genes, is associated with lung cancer prognosis and survival [1], although conflicting results of the association of this region with prognosis, in particular of the MYCL1-EcoRI polymorphism, have been reported [2,3]. Indeed, association of MYCL1-EcoRI with lung cancer patients' survival was observed in all of 4 studies of Asians, but in none of 3 studies on Caucasians [3]. The discrepancies might reflect ethnic differences in allelic frequencies of the functional genetic variants mapping in this locus, as suggested by the significant difference between Caucasian and Asian subjects in the frequencies of several SNPs located in the TRIT1, MYCL1, and MFSD2A gene [1].Modulation of expression of a gene mapping in the MYCL1 region may represent a mechanism underlying the association of this region with cancer patients' survival. Indeed, MYCL1 expression is not detected in normal or tumor tissue. Both the TRIT1 and MFSD2A genes are downregulated in lung adenocarcinomas (ADCA), whereas overexpression of either gene has tumor-suppressor effects [1,4,5]. The MFSD2A gene was also strongly downregulated in a panel of non-small cell lung cancer (NSCLC) cell lines, where it inhibits cell ad
Teacher as Learning Facilitator in ELT  [cached]
Badea Elena Codruta
EIRP Proceedings , 2012,
Abstract: The classroom is the magic active scenery where many educational things take place simultaneously.Intellectual, emotional, socio-cultural, motivational and curricular factors corroborate their influence onclassroom environments, whether we deal with traditional models of teaching or with the constructivistapproaches. The growing demand for language teachers, English in particular, has determined a new vision oflanguage teaching strategies. The cutting-edge technology has created a fertile ground which successfullyfosters the teacher –student communication, emphasizing the teacher’s role to guide students and to generate achange in their learning approach and in eliciting useable knowledge. This way, the teacher has a larger abilityto convert knowledge into practical information that is of real help and value to students. Students are involvedin a continuous educational scheme and are tested on what they have learned. This ensures they can alwaysenjoy the benefits of active learning from expert teachers. The present paper deals with a brief analysis of therole of teacher as learning facilitator and its importance for student acquisition process, eliciting some strategiesin support of collaborative and student-centered learning.
The practical theologian as decentred but influential facilitator
H. Elmo Pienaar,Julian C. Müller
HTS Theological Studies/Teologiese Studies , 2012,
Abstract: Since the 1970s along with the resurgence in practical philosophy new possibilities opened up in our understanding of the place for and purpose of practical theology. The repositioning of practical theology as a fully worthy discipline was important to find its voice amongst theological peer disciplines. Against this background, it was argued that the full measure of what the discipline can contribute, especially outside of the ministry context, has not yet been fully developed or practiced. Towards this end the presentation’s main contention was put forward, in that it is vital for the practical theologian to take up a role of an inscribed facilitator. It signifies a shift from practical theology to practical theologian and is exemplified by the practice of a facilitative approach in, and to practical theology.
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