HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Barter, Matt J., Pybus, Leon, Litherland, Gary J., Rowan, Andrew D., Clark, Ian M., Edwards, Dylan R., Cawston, Tim E. and Young, David A. (2010) HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes. Matrix Biology, 29 (7). pp. 602-612. ISSN 1569-1802

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Abstract

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-ß signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-ß-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-ß, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-ß induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-ß induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-ß-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-ß-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-ß. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-ß and for the subsequent gene induction dependent on these signalling pathways.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Users 2731 not found.
Date Deposited: 10 May 2011 13:24
Last Modified: 21 Jul 2020 23:33
URI: https://ueaeprints.uea.ac.uk/id/eprint/30146
DOI: 10.1016/j.matbio.2010.05.002

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