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RESEARCH PAPER

A mechanism of AP-1 suppression through interaction of c-Fos with lamin A/C

¹ Laboratory of Vascular Biology, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Valencia 46010, Spain; ² Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain; ³ Laboratory of Cytomics, Centro de Investigación Príncipe Felipe, and Universidad de Valencia, Valencia 46010, Spain; ⁴ Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida 32610, USA

AP-1 (Activating Protein 1) transcription factor activity is tightly regulated at multiple levels, including dimer formation (i.e., Fos/Jun). Here we show that the intermediate filament protein lamin A/C suppresses AP-1 function through direct interaction with c-Fos, and that both proteins can interact and colocalize at the nuclear envelope (NE) in mammalian cells. Perinuclear localization of c-Fos is absent in Lmna-null cells but can be restored by lamin A overexpression. In vitro, preincubation of c-Fos with lamin A prior to the addition of c-Jun inhibits AP-1 DNA-binding activity. In vivo, overexpression of lamin A reduces the formation of c-Fos/c-Jun heterodimers, and suppresses AP-1 DNA-binding and transcriptional activity. Notably, c-Fos colocalizes with lamin A/C at the NE in starvation-synchronized quiescent cells lacking detectable AP-1 DNA binding. In contrast, serum-induced AP-1 DNA-binding activity coincides with abundant nucleoplasmic c-Fos expression without changes in lamin A/C localization. We also found that Lmna-null cells display enhanced proliferation. In contrast, lamin A overexpression causes growth arrest, and ectopic c-Fos partially overcomes lamin A/C-induced cell cycle alterations. We propose lamin A/C-mediated c-Fos sequestration at the NE as a novel mechanism of transcriptional and cell cycle control.

[Keywords: c-Fos; AP-1; leucine zipper; lamin A/C; transcriptional regulation; nuclear envelope]

Received May 2, 2005; revised version accepted November 29, 2005.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.349506.

⁵ These authors contributed equally to this work.

⁶ Present address: Department of Chemistry, Biochemistry, and Molecular Biology, Universidad Cardenal Herrera-CEU, Moncada, Valencia 46110, Spain

⁷ Present address: Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna A-1090, Austria.

⁸ Corresponding author.

E-MAIL vandres{at}ibv.csic.es; FAX 34-96-3391751.

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