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dc.contributor.authorSamuel, Glady Hen_US
dc.contributor.authorBujor, Andreea Men_US
dc.contributor.authorNakerakanti, Sashidhar Sen_US
dc.contributor.authorHant, Faye Nen_US
dc.contributor.authorTrojanowska, Mariaen_US
dc.date.accessioned2012-01-09T14:21:32Z
dc.date.available2012-01-09T14:21:32Z
dc.date.copyright2010en_US
dc.date.issued2010-12-06en_US
dc.identifier.citationSamuel, Glady H, Andreea M Bujor, Sashidhar S Nakerakanti, Faye N Hant, Maria Trojanowska. "Autocrine Transforming Growth Factor β Signaling Regulates Extracellular Signal-regulated Kinase 1/2 Phosphorylation via Modulation of Protein Phosphatase 2A Expression in Scleroderma Fibroblasts" Fibrogenesis & Tissue Repair 3:25. (2010)en_US
dc.identifier.issn1755-1536en_US
dc.identifier.urihttp://hdl.handle.net/2144/2758
dc.description.abstractBACKGROUND. During scleroderma (SSc) pathogenesis, fibroblasts acquire an activated phenotype characterized by enhanced production of extracellular matrix (ECM) and constitutive activation of several major signaling pathways including extracellular signal-related kinase (ERK1/2). Several studies have addressed the role of ERK1/2 in SSc fibrosis however the mechanism of its prolonged activation in SSc fibroblasts is still unknown. Protein phosphatase 2A (PP2A) is a key serine threonine phosphatase responsible for dephosphorylation of a wide array of signaling molecules. Recently published microarray data from cultured SSc fibroblasts suggests that the catalytic subunit (C-subunit) of PP2A is downregulated in SSc. In this study we examined the role and regulation of PP2A in SSc fibroblasts in the context of ERK1/2 phosphorylation and matrix production. RESULTS. We show for the first time that PP2A mRNA and protein expression are significantly reduced in SSc fibroblasts and correlate with an increase in ERK1/2 phosphorylation and collagen expression. Furthermore, transforming growth factor β (TGFβ), a major profibrotic cytokine implicated in SSc fibrosis, downregulates PP2A expression in healthy fibroblasts. PP2A-specific small interfering RNA (siRNA) was utilized to confirm the role of PP2A in ERK1/2 dephosphorylation in dermal fibroblasts. Accordingly, blockade of autocrine TGFβ signaling in SSc fibroblasts using soluble recombinant TGFβ receptor II (SRII) restored PP2A levels and decreased ERK1/2 phosphorylation and collagen expression. In addition, we observed that inhibition of ERK1/2 in SSc fibroblasts increased PP2A expression suggesting that ERK1/2 phosphorylation also contributes to maintaining low levels of PP2A, leading to an even further amplification of ERK1/2 phosphorylation. CONCLUSIONS. Taken together, these studies suggest that decreased PP2A levels in SSc is a result of constitutively activated autocrine TGFβ signaling and could contribute to enhanced phosphorylation of ERK1/2 and matrix production in SSc fibroblasts.en_US
dc.description.sponsorshipNational Institutes of Health (AR-44883)en_US
dc.language.isoenen_US
dc.publisherBioMed Centralen_US
dc.rightsCopyright 2010 Samuel et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
dc.titleAutocrine Transforming Growth Factor β Signaling Regulates Extracellular Signal-regulated Kinase 1/2 Phosphorylation via Modulation of Protein Phosphatase 2A Expression in Scleroderma Fibroblastsen_US
dc.typearticleen_US
dc.identifier.doi10.1186/1755-1536-3-25en_US
dc.identifier.pubmedid21134273en_US
dc.identifier.pmcid3008687en_US


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