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Liwak U.,Ottawa Hospital Research Institute | Liwak U.,University of Ottawa | Thakor N.,Ottawa Hospital Research Institute | Jordan L.E.,Ottawa Hospital Research Institute | And 8 more authors.
Molecular and Cellular Biology

Apoptosis can be regulated by extracellular signals that are communicated by peptides such as fibroblast growth factor 2 (FGF-2) that have important roles in tumor cell proliferation. The prosurvival effects of FGF-2 are transduced by the activation of the ribosomal protein S6 kinase 2 (S6K2), which increases the expression of the antiapoptotic proteins X chromosome-linked Inhibitor of Apoptosis (XIAP) and Bcl-xL. We now show that the FGF-2-S6K2 prosurvival signaling is mediated by the tumor suppressor programmed cell death 4 (PDCD4). We demonstrate that PDCD4 specifically binds to the internal ribosome entry site (IRES) elements of both the XIAP and Bcl-xL messenger RNAs and represses their translation by inhibiting the formation of the 48S translation initiation complex. Phosphorylation of PDCD4 by activated S6K2 leads to the degradation of PDCD4 and thus the subsequent derepression of XIAP and Bcl-xL translation. Our results identify PDCD4 as a specific repressor of the IRES-dependent translation of cellular mRNAs (such as XIAP and Bcl-xL) that mediate FGF-2-S6K2 prosurvival signaling and provide further insight into the role of PDCD4 in tumor suppression. © 2012, American Society for Microbiology. Source

Steeves C.H.,Dalhousie University | Potrykus J.,Dalhousie University | Barnett D.A.,Atlantic Cancer Research Institute | Bearne S.L.,Dalhousie University

The anaerobic, Gram-negative bacillus Fusobacterium nucleatum plays a vital role in oral biofilm formation and the development of periodontal disease. The organism plays a central bridging role between early and late colonizers within dental plaque and plays a protective role against reactive oxygen species. Using a two-dimensional gel electrophoresis and mass spectrometry approach, we have annotated 78 proteins within the proteome of F. nucleatum subsp. nucleatum and identified those proteins whose apparent intracellular concentrations change in response to either O2- or H2O2-induced oxidative stress. Three major protein systems were altered in response to oxidative stress: (i) proteins of the alkyl hydroperoxide reductase/thioredoxin reductase system were increased in intracellular concentration; (ii) glycolytic enzymes were modified by oxidation (i.e. D-glyceraldehyde 3-phosphate dehydrogenase, and fructose 6-phosphate aldolase) or increased in intracellular concentration, with an accompanying decrease in ATP production; and (iii) the intracellular concentrations of molecular chaperone proteins and related proteins (i.e. ClpB, DnaK, HtpG, and HrcA) were increased. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Shukla P.K.,CSIR - Central Electrochemical Research Institute | Kumar A.,Atlantic Cancer Research Institute
Microbial Pathogenesis

There has been an increase in the cases of fungal resistance against many antifungal drugs and an effective alternative mode in the form of immunotherapy is being considered as new hope. The adhesion of Aspergillus fumigatus conidia to the host components is one of the prime factors to cause aspergillosis. Carbohydrate components or glycoproteins present on the cell surface play an important role in interaction of the organism to the host and leads to adhesion. Any substance which is capable of disrupting this interaction may be a vital tool for the fungal clearance and hence may protect the host from infections caused by the fungus. In this study, a murine monoclonal antibody IgM generated against the secretory antigens of A.fumigatus, was found to be specific to a common epitope containing glyco-moieties of the various proteins and exhibited anti-adhesive potential invitro. © 2015 Elsevier Ltd. Source

Gillis L.D.,Atlantic Cancer Research Institute | Lewis S.M.,Atlantic Cancer Research Institute | Lewis S.M.,Dalhousie University | Lewis S.M.,University of New Brunswick

eIF3e/Int6 is a component of the multi-subunit eIF3 complex, which binds directly to the 40S ribosome to facilitate ribosome recruitment to mRNA and hence protein synthesis. Reduced expression of eIF3e/Int6 has been found in up to 37% of human breast cancers, and expression of a truncated mutant version of the mouse eIF3e/Int6 protein leads to malignant transformation of normal mammary cells. These findings suggest that eIF3e/Int6 is a tumor suppressor; however, a recent study has reported that a reduction of eIF3e/Int6 expression in breast cancer cells leads to reduced translation of oncogenes, suggesting that eIF3e/Int6 may in fact have an oncogenic role in breast cancer. To gain a better understanding of the role of eIF3e/Int6 in breast cancer, we have examined the effects of decreased eIF3e/Int6 expression in an immortalized breast epithelial cell line, MCF-10A. Surprisingly, we find that decreased expression of eIF3e/Int6 causes breast epithelial cells to undergo epithelial-to-mesenchymal transition (EMT). We show that EMT induced by a decrease in eIF3e/Int6 expression imparts invasive and migratory properties to breast epithelial cells, suggesting that regulation of EMT by eIF3e/Int6 may have an important role in breast cancer metastasis. Furthermore, we show that reduced eIF3e/Int6 expression in breast epithelial cells causes a specific increase in the expression of the key EMT regulators Snail1 and Zeb2, which occurs at both the transcriptional and post-transcriptional levels. Together, our data indicate a novel role of eIF3e/Int6 in the regulation of EMT in breast epithelial cells and support a tumor suppressor role of eIF3e/Int6. © 2013 Macmillan Publishers Limited. Source

Barnett D.A.,Atlantic Cancer Research Institute | Barnett D.A.,Mount Allison University | Ouellette R.J.,Atlantic Cancer Research Institute | Ouellette R.J.,Universite de Sherbrooke
Rapid Communications in Mass Spectrometry

Cylindrical geometry high-field asymmetric waveform ion mobility spectrometry (FAIMS) focuses and separates gas-phase ions at atmospheric pressure and room (or elevated) temperature. Addition of helium to a nitrogen-based separation medium offers significant advantages for FAIMS including improved resolution, selectivity and sensitivity. Aside from gas composition, ion transmission through FAIMS is governed by electric field strength (E/N) that is determined by the applied voltage, the analyzer gap width, atmospheric pressure and electrode temperature. In this study, the analyzer width of a cylindrical FAIMS device is varied from 2.5 to 1.25 mm to achieve average electric field strengths as high as 187.5 Townsend (Td). At these electric fields, the performance of FAIMS in an N 2 environment is dramatically improved over a commercial system that uses an analyzer width of 2.5 mm in 1:1 N 2/He. At fields of 162 Td using electrodes at room temperature, the average effective temperature for the [M + 2 H] 2+ ion of angiotensin II reaches 365 K. This has a dramatic impact on the curtain gas flow rate, resulting in lower optimum flows and reduced turbulence in the ion inlet. The use of narrow analyzer widths in a N 2 carrier gas offers previously unattainable baseline resolution of the [M + 2 H] 2+ and [M + 3 H] 3+ ions of angiotensin II. Comparisons of absolute ion current with FAIMS to conventional electrospray ionization (ESI) are as high as 77% with FAIMS versus standard ESI-MS. Copyright © 2011 John Wiley & Sons, Ltd. Source

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