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Published 10 April 2006. doi:10.1083/jcb.200511149
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 1, 83-93
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Article

 Lamina-associated polypeptide 2{alpha} regulates cell cycle progression and differentiation via the retinoblastoma–E2F pathway

Daniela Dorner1, Sylvia Vlcek1, Nicole Foeger1, Andreas Gajewski1, Christian Makolm1, Josef Gotzmann1, Christopher J. Hutchison2, and Roland Foisner1

1 Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, A-1030 Vienna, Austria
2 Department of Biological Sciences, University of Durham, Durham DH1 3HP, United Kingdom

Correspondence to Roland Foisner: roland.foisner{at}meduniwien.ac.at

Lamina-associated polypeptide (LAP) 2{alpha} is a nonmembrane-bound LAP2 isoform that forms complexes with nucleoplasmic A-type lamins. In this study, we show that the overexpression of LAP2{alpha} in fibroblasts reduced proliferation and delayed entry into the cell cycle from a G0 arrest. In contrast, stable down-regulation of LAP2{alpha} by RNA interference accelerated proliferation and interfered with cell cycle exit upon serum starvation. The LAP2{alpha}-linked cell cycle phenotype is mediated by the retinoblastoma (Rb) protein because the LAP2{alpha} COOH terminus directly bound Rb, and overexpressed LAP2{alpha} inhibited E2F/Rb-dependent reporter gene activity in G1 phase in an Rb-dependent manner. Furthermore, LAP2{alpha} associated with promoter sequences in endogenous E2F/Rb-dependent target genes in vivo and negatively affected their expression. In addition, the expression of LAP2{alpha} in proliferating preadipocytes caused the accumulation of hypophosphorylated Rb, which is reminiscent of noncycling cells, and initiated partial differentiation into adipocytes. The effects of LAP2{alpha} on cell cycle progression and differentiation may be highly relevant for the cell- and tissue-specific phenotypes observed in laminopathic diseases.

Abbreviations used in this paper: LAP, lamina-associated polypeptide; LEM, LAP2–emerin–MAN1; MEF, mouse embryonic fibroblast; PPAR{gamma}, peroxisome proliferator–activated receptor {gamma}; Rb, retinoblastoma; shRNA, short hairpin RNA; T3, triiodothyronine; TKO, triple knockout.


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