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


CONCLUSIONS
ERK is a potential target for the pharmacological treatment of cardiomyopathy caused by mutations in the genes encoding emerin and A-type lamins.
Muchir
Antoine
A
Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, 10 Floor, Room 508, New York, NY 10032, USA.
Wu
Wei
W
Worman
Howard J
HJ
D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000037:antagonists & inhibitors / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics
D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C092710:emerin; D020928:Mitogen-Activated Protein Kinases