Abstract |
Mutation R453W in A-type lamins, that are major nuclear envelope proteins, generates Emery-Dreifuss muscular dystrophy. We previously showed that mouse myoblasts expressing R453W-lamin A incompletely exit the cell cycle and differentiate into myocytes with a low level of multinucleation. Here we attempted to improve differentiation by treating these cells with a mixture of PD98059, an extracellular-regulated kinase (ERK) kinase (also known as mitogen-activated kinase, MEK) inhibitor, and insulin-like growth factor-II, an activator of phosphoinositide 3-kinase. We show that mouse myoblasts expressing R453W-lamin A were sensitive to the drug treatment as shown by (i) an increase in multinucleation, (ii) downregulation of proliferation markers ( cyclin D1, hyperphosphorylated Rb), (iii) upregulation of myogenin, and (iv) sustained activation of p21 and cyclin D3. However, nuclear matrix anchorage of p21 and cyclin D3 in a complex with hypophosphorylated Rb that is critical to trigger cell cycle arrest and myogenin induction was deficient and incompletely restored by drug treatment. As the turn-over of R453W-lamin A at the nuclear envelope was greatly enhanced, we propose that R453W-lamin A impairs the capacity of the nuclear lamina to serve as scaffold for substrates of the MEK-ERK pathway and for MyoD-induced proteins that play a role in the differentiation process.
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Authors | Catherine Favreau, Erwan Delbarre, Jean-Claude Courvalin, Brigitte Buendia |
Journal | Experimental cell research
(Exp Cell Res)
Vol. 314
Issue 6
Pg. 1392-405
(Apr 01 2008)
ISSN: 0014-4827 [Print] United States |
PMID | 18294630
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antigens, CD1
- CD3 Complex
- Cyclin-Dependent Kinase Inhibitor p21
- Lamin Type A
- Mutant Proteins
- Myogenin
- Protein Kinase Inhibitors
- Retinoblastoma Protein
- Green Fluorescent Proteins
- Insulin-Like Growth Factor II
- Phosphatidylinositol 3-Kinases
- Extracellular Signal-Regulated MAP Kinases
- Mitogen-Activated Protein Kinases
- Mitogen-Activated Protein Kinase Kinases
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Topics |
- Animals
- Antigens, CD1
(metabolism)
- CD3 Complex
(metabolism)
- Cell Death
(drug effects)
- Cell Differentiation
(drug effects)
- Cell Line
- Cell Proliferation
(drug effects)
- Cyclin-Dependent Kinase Inhibitor p21
(metabolism)
- Extracellular Signal-Regulated MAP Kinases
(antagonists & inhibitors)
- Green Fluorescent Proteins
(metabolism)
- Insulin-Like Growth Factor II
(pharmacology)
- Lamin Type A
(metabolism)
- Mice
- Mitogen-Activated Protein Kinase Kinases
(antagonists & inhibitors)
- Mitogen-Activated Protein Kinases
(antagonists & inhibitors)
- Muscular Dystrophy, Emery-Dreifuss
(enzymology, pathology)
- Mutant Proteins
(metabolism)
- Mutation
(genetics)
- Myoblasts
(cytology, drug effects, enzymology)
- Myogenin
(metabolism)
- Nuclear Lamina
(drug effects, metabolism)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Phosphorylation
(drug effects)
- Protein Kinase Inhibitors
(pharmacology)
- Retinoblastoma Protein
(metabolism)
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