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Human Molecular Genetics Advance Access originally published online on August 22, 2005
Human Molecular Genetics 2005 14(19):2839-2849; doi:10.1093/hmg/ddi316
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

A-type lamins are essential for TGF-ß1 induced PP2A to dephosphorylate transcription factors

J.H. Van Berlo1,4,{dagger}, J.W. Voncken2,{dagger}, N. Kubben1,2,4, J.L.V. Broers3, R. Duisters1,4, R.E.W. van Leeuwen1,4, H.J.G.M. Crijns1,4, F.C.S. Ramaekers3, C.J. Hutchison5 and Y.M. Pinto1,4,*

1Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, 2Department of Molecular Genetics, Research Institute Growth and Development and 3Department of Molecular Cell Biology, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands and 4Department of Cardiology, University Hospital Maastricht, Maastricht, The Netherlands and 5School of Biological and Biomedical Sciences, The University of Durham, Durham, UK

* To whom correspondence should be addressed at: Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht (CARIM), University Maastricht, P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Tel: +31 433877097; Fax: +31 433871055; Email: y.pinto{at}cardio.azm.nl

Received June 1, 2005; Revised August 1, 2005; Accepted August 11, 2005

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. As transforming growth factor-ß1 (TGF-ß1) signalling impinges on the retinoblastoma protein (pRB) and SMADs, we tested the hypothesis that lamins modulate cellular responses to TGF-ß1 signalling, via the regulation of these transcription factors in mesenchymal cells. Here, we report that A-type lamins are essential for the inhibition of fibroblast proliferation by TGF-ß1. TGF-ß1 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-ß1 on collagen production, a marker of mesenchymal differentiation. Our findings implicate lamin A/C in control of gene activity downstream of TGF-ß1, via nuclear phosphatases such as PP2A. This biological function provides a novel explanation for the observed mesenchymal dysfunction in laminopathies.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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