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Human Molecular Genetics Advance Access published online on August 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi316
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 1, 2005
Revised August 1, 2005
Accepted August 11, 2005

Article

A-type lamins are essential for TGF-{beta}1 induced PP2A to dephosphorylate transcription factors

J H Van Berlo 1, J W Voncken 2, Kubben N 3, J LV Broers 4, R Duisters 1, R EW van Leeuwen 1, H JGM Crijns 1, F CS Ramaekers 4, C J Hutchison 5, and Y M Pinto 6*

1 Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University Maastricht and Department of Cardiology, University Hospital Maastricht, Maastricht, the Netherlands
2 Department of Molecular Genetics, Research Institute Growth and Development, University Maastricht, the Netherlands
3 Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University Maastricht and Department of Cardiology, University Hospital Maastricht, Maastricht, the Netherlands; Department of Molecular Genetics, Research Institute Growth and Development, University Maastricht, the Netherlands
4 Department of Molecular Cell Biology, Cardiovascular Research Institute Maastricht, University Maastricht, the Netherlands
5 School of Biological and Biomedical Sciences, The University of Durham, Durham, United Kingdom
6 Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University Maastricht and Department of Cardiology, University Hospital Maastricht, P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, the Netherlands

* To whom correspondence should be addressed.
Y M Pinto, E-mail: y.pinto{at}cardio.azm.nl


  Abstract

Diseases caused by mutations in lamins A and C (laminopathies) suggest a crucial role for A-type lamins in different cellular processes. Laminopathies mostly affect tissues of mesenchymal origin. Since transforming growth factor (TGF) {beta}1 signalling impinges on the retinoblastoma protein (pRB) and SMADs, we tested the hypothesis that lamins modulate cellular responses to TGF- {beta}1 signalling, via regulation of these transcription factors in mesenchymal cells. We here report that A-type lamins are essential for the inhibition of fibroblast proliferation by TGF-{beta}1. TGF-{beta}1 dephosphorylated pRB through PP2A, both of which, we show, are associated with lamin A/C. In addition, lamin A/C modulates the effect of TGF-{beta}1 on Collagen production, a marker of mesenchymal differentiation. Our findings implicate lamin A/C in control of gene activity downstream of TGF-{beta}1, via nuclear phosphatases such as PP2A. This biological function provides a novel explanation for the observed mesenchymal dysfunction in laminopathies.


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