A mechanism of AP-1 suppression through interaction of c-Fos with lamin A/C.
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.
Ivorra
Carmen
C
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.
Kubicek
Markus
M
González
José M
JM
Sanz-González
Silvia M
SM
Alvarez-Barrientos
Alberto
A
O'Connor
José-Enrique
JE
Burke
Brian
B
Andrés
Vicente
V
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops / Q000378:metabolism; D004274:DNA, Recombinant; D019281:Dimerization; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D034881:Nuclear Lamina / Q000378:metabolism; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
D050976:Basic-Leucine Zipper Transcription Factors; D004274:DNA, Recombinant; D034904:Lamin Type A; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1