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Published online January 16, 2007
doi:10.1083/jcb.200606139
The Journal of Cell Biology, Vol. 176, No. 2, 163-172
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Pekovic et al.
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Article

 Nucleoplasmic LAP2{alpha}–lamin A complexes are required to maintain a proliferative state in human fibroblasts

Vanja Pekovic1, Jens Harborth2, Jos L.V. Broers3, Frans C.S. Ramaekers3, Baziel van Engelen4, Martin Lammens4, Thomas von Zglinicki5, Roland Foisner6, Chris Hutchison1, and Ewa Markiewicz1

1 School of Biological and Biomedical Sciences, University of Durham, Durham DH1 3LE, England, UK
2 Alnylam Pharmaceuticals, Inc., Bioanalytics and Preclinical, Cambridge, MA 02142
3 Department of Molecular Cell Biology, Cardiovascular Research Institute Maastricht, and Research Institute Growth and Development, University of Maastricht, Maastricht, Netherlands
4 Neuromuscular Centre Nijmegen, Institute of Neurology, University Medical Centre, Nijmegen, Netherlands
5 Henry Wellcome Laboratory for Biogerontology Research, University of Newcastle, Newcastle General Hospital, Newcastle-upon-Tyne NE4 6BE, England, UK
6 Max F. Perutz Laboratories, Medical University Vienna, 1030 Vienna, Austria

Correspondence to Chris Hutchison: c.j.hutchison{at}durham.ac.uk

In human diploid fibroblasts (HDFs), expression of lamina-associated polypeptide 2 {alpha} (LAP2{alpha}) upon entry and exit from G0 is tightly correlated with phosphorylation and subnuclear localization of retinoblastoma protein (Rb). Phosphoisoforms of Rb and LAP2{alpha} are down-regulated in G0. Although RbS780 phosphoform and LAP2{alpha} are up-regulated upon reentry into G1 and colocalize in the nucleoplasm, RbS795 migrates between nucleoplasmic and speckle compartments. In HDFs, which are null for lamins A/C, LAP2{alpha} is mislocalized within nuclear aggregates, and this is correlated with cell cycle arrest and accumulation of Rb within speckles. Nuclear retention of nucleoplasmic Rb during G1 phase but not of speckle-associated Rb depends on lamin A/C. siRNA knock down of LAP2{alpha} or lamin A/C in HDFs leads to accumulation of Rb in speckles and G1 arrest, probably because of activation of a cell cycle checkpoint. Our results suggest that LAP2{alpha} and lamin A/C are involved in controlling Rb localization and phosphorylation, and a lack or mislocalization of either protein leads to cell cycle arrest in HDFs.

Abbreviations used in this paper: HDF, human diploid fibroblast; LAP2, lamina-associated polypeptide 2; MEF, mouse embryonic fibroblast; NCS, newborn calf serum; NE, nuclear envelope; Rb, retinoblastoma protein.


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