Unknown,Transcriptomics,Genomics,Proteomics

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The effect of 2-AA on P. aeruginosa PA14 and its mutants

ABSTRACT: The pqs operon of the bacteria P. aeruginosa is responsible for the production of at least 60 secreted compounds mainly hidroxy-quinolones (HAQs). Some of them, like PQS and HHQ, were found to be important signal that control the virulence of the bacteria. We have discover that one of the most abandon molecule produced by the pqs operon, 2 aminoacetophenone (2-AA), a volatile molecule serves as a unique signal. In contrast to the previous described PQS and HHQ, 2-AA is downregulating virulence and acute phase proteins and upregulating chronic phase proteins. In addition we have found that 2-AA promotes the formation of persisters cells that antibiotic tolerant. we have compared the genes profile of wild-type PA14 strain and its derivatives topA which lacks Topoisomerase I and pqsA that do not produces HAQs or 2-AA to cultures that were treated with 3mM of 2-AA. Cell were grown with and without 2-AA (3mM) to OD 2.0.

ORGANISM(S): Pseudomonas aeruginosa PA14

SUBMITTER: Laurence Rahme

PROVIDER: E-GEOD-24036 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Arachidonic acid (AA) is a polyunsaturated fatty acid present at high concentrations in the ovarian cancer (OC) microenvironment and is associated with poor clinical outcome. In the present study, we elucidate a potential link between AA and pro-tumorigenic macrophage polarization. Methods: AA-triggered signal transduction was studied in primary monocyte-derived macrophages (MDMs) by phosphoproteomics, transcriptional profiling, measurement of intracellular Ca2+ accumulation and reactive oxygen species production in conjunction with bioinformatic analyses. Functional effects were investigated by actin filament staining, quantification of macropinocytosis and analysis of extracellular vesicle release. Results: We identified the ASK1 - p38 (MAPK13/14) axis as a central constituent of signal transduction pathways triggered by non-metabolized AA. This pathway was induced by the Ca2+-triggered activation of calmodulin kinase II, and to a minor extent by ROS generation in a subset of donors. Activated p38 in turn was linked to a transcriptional stress response associated with a poor relapse-free survival. Consistent with the phosphorylation of the p38 substrate HSP27 and the (de)phosphorylation of multiple regulators of Rho family GTPases, AA impaired actin filament organization and inhibited actin-driven macropinocytosis. AA also affected the phosphorylation of proteins regulating vesicle biogenesis, and consistently, AA enhanced the release of tetraspanin-containing exosomes. Finally, we identified phospholipase A2 Group 2A (PLA2G2A) as the clinically most relevant enzyme producing extracellular AA, providing further potentially theranostic options. Conclusion: Our results suggest that AA contributes to an unfavorable clinical outcome of OC by promoting the pro-tumorigenic phenotype of tumor-associated macrophages. Besides critical AA-regulated signal transduction proteins identified in the present study, PLA2G2A might represent a potential prognostic tool and therapeutic target to interfere with OC progression.

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The effect of 2-AA on P. aeruginosa PA14 and its mutants

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