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Biochim Biophys Acta. 2009 Jan;1792(1):75-81. doi: 10.1016/j.bbadis.2008.10.012. Epub 2008 Nov 5.

Reduced expression of A-type lamins and emerin activates extracellular signal-regulated kinase in cultured cells.

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1
Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, 10 Floor, Room 508, New York, NY 10032, USA.

Abstract

BACKGROUND:

Mutations in genes encoding A-type lamins and emerin cause cardiomyopathy and muscular dystrophy. We previously showed activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) cascade in hearts of mice with mutations in these genes. Here, we tested the hypothesis that reducing A-type lamins and emerin in cultured cells activate ERK signaling.

METHODS:

We used siRNA to knockdown A-type lamins and emerin in HeLa and C2C12 cells. Activation of ERK was assessed by immunoblotting and immunofluorescence microscopy with antibodies against phosphorylated protein and by using real-time RT-PCR to measure RNAs encoded by genes for transcription factors stimulated by ERK.

RESULTS:

Knockdown of A-type lamins and emerin in HeLa and C2C12 stimulated phosphorylation and nuclear translocation of ERK as well as activation of genes encoding downstream transcription factors. A MAPK/ERK kinase (MEK) inhibitor reduced ERK phosphorylation in cells with reduced expression of A-type lamins and emerin.

CONCLUSIONS:

These results provide proof for the hypothesis that altered expression of emerin and A-type lamins activates ERK signaling, which in turn can cause cardiomyopathy.

GENERAL SIGNIFICANCE:

ERK is a potential target for the pharmacological treatment of cardiomyopathy caused by mutations in the genes encoding emerin and A-type lamins.

PMID:
19022376
PMCID:
PMC2646592
DOI:
10.1016/j.bbadis.2008.10.012
[Indexed for MEDLINE]
Free PMC Article
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