| LEOPARD-type SHP2 mutant Gln510Glu attenuates cardiomyocyte differentiation and promotes cardiac hypertrophy via dysregulation of Akt/GSK3{beta}/{beta}-catenin signaling. | |
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MedLine Citation:
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PMID: 21803945 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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LEOPARD syndrome (LS) is an autosomal dominant inherited multisystemic disorder. Most cases involve mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP2. LS frequently causes severe hypertrophic cardiomyopathy (HCM), even from the fetal period. However, the molecular pathogenesis has not been clearly elucidated. Here, we analyzed the roles of the LS-type SHP2 mutant Gln510Glu (Q510E), which showed the most severe type of HCM in LS, in cardiomyocyte differentiation, and in morphological changes. We generated mutant P19CL6 cell lines, the most convenient cardiomyocyte differentiation model, which continuously expressed SHP2-Q510E, SHP2-D61N (Noonan-type mutant), wild-type SHP2, and green fluorescent protein (GFP) (native SHP2 expression only). The SHP2-Q510E mutant P19CL6 cells showed significant attenuation of myofibrillogenesis, with increased proliferative activity. Mature cardiomyocytes from the SHP2-Q510E mutant were significantly larger than those of controls and the other mutants. However, the expression of the cardiac-specific transcriptional factors, Gata4, Tbx5, and Nkx2.5, did not differ significantly between the LS-type SHP2-Q510E mutants, and the other mutants and controls. Our results indicate that SHP2-Q510E mutants can differentiate into cardiac progenitors, but are inhibited from undergoing terminal differentiation into mature cardiomyocytes. By contrast, Akt and glycogen synthase kinase (GSK) 3β phosphorylation were up-regulated, and nuclear β-catenin at the late stage of differentiation was highly accumulated in SHP2-Q510E mutant P19CL6 cells. Supplementation with the phosphoinositide 3-kinase (PI3K)/Akt inhibitor LY294002 during the late stage of differentiation was found to partially restore myofibrillogenesis, while suppressing the increase in size of individual mature cardiomyocytes derived from the SHP2-Q510E mutants. Our findings suggest that dysregulation of the Akt/GSK3β/β-catenin pathway can contribute to the pathogenesis of HCM in LS patients, not only through hypertrophic changes in individual cardiac cells, but also via the expansion of cardiac progenitors. |
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Authors:
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Hidekazu Ishida; Shigetoyo Kogaki; Jun Narita; Hiroaki Ichimori; Nobutoshi Nawa; Yoko Okada; Kunihiko Takahashi; Keiichi Ozono |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-7-29 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: - ISSN: 1522-1539 ISO Abbreviation: - Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-8-1 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1Department of Pediatrics, Osaka University Graduate School of Medicine. |
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