Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy

Minetti, Carlo; Sotgia, Federica; Bruno, Claudio; Scartezzini, Paolo; Broda, Paolo; Bado, M.; Masetti, Emiliana; Mazzocco, Michela; Egeo, Aliana; Donati, Maria Alice; Volonté, Daniela; Galbiati, Ferruccio; Cordone, G; Bricarelli, Franca Dagna; Lisanti, Michael P.; Zara, Federico

doi:10.1038/ng0498-365

Cited by 533 publications

(448 citation statements)

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“…Caveolin-1 and caveolin-2 are coexpressed in many cell types, including adipocytes, endothelial cells, epithelial cells, and fibroblasts (9). In contrast, caveolin-3 expression is essentially restricted to skeletal and smooth muscle cells, as well as cardiac myocytes (10)(11)(12)(13)(14)(15)(16)(17)(18). The direct interaction with caveolin-1 results in the inhibition of a number of signaling molecules, such as G-protein a subunit, Ras, nitric oxide synthase, protein kinase C, and protein kinase A (2,7,10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress Induces Premature Senescence by Stimulating Caveolin-1 Gene Transcription through p38 Mitogen-Activated Protein Kinase/Sp1–Mediated Activation of Two GC-Rich Promoter Elements

et al. 2006

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Cellular senescence is believed to represent a natural tumor suppressor mechanism. We have previously shown that upregulation of caveolin-1 was required for oxidative stressinduced premature senescence in fibroblasts. However, the molecular mechanisms underlying caveolin-1 up-regulation in senescent cells remain unknown. Here, we show that subcytotoxic oxidative stress generated by hydrogen peroxide application promotes premature senescence and stimulates the activity of a (À1,296) caveolin-1 promoter reporter gene construct in fibroblasts. Functional deletion analysis mapped the oxidative stress response elements of the mouse caveolin-1 promoter to the sequences À244/À222 and À124/À101. The hydrogen peroxide-mediated activation of both Cav-1 (À244/ À222) and Cav-1 (À124/À101) was prevented by the antioxidant quercetin. Combination of electrophoretic mobility shift studies, chromatin immunoprecipitation analysis, Sp1 overexpression experiments, as well as promoter mutagenesis identifies enhanced Sp1 binding to two GC-boxes at À238/ À231 and À118/À106 as the core mechanism of oxidative stress-triggered caveolin-1 transactivation. In addition, signaling studies show p38 mitogen-activated protein kinase (MAPK) as the upstream regulator of Sp1-mediated activation of the caveolin-1 promoter following oxidative stress. Inhibition of p38 MAPK prevents the oxidant-induced Sp1-mediated up-regulation of caveolin-1 protein expression and development of premature senescence. Finally, we show that oxidative stress induces p38-mediated up-regulation of caveolin-1 and premature senescence in normal human mammary epithelial cells but not in MCF-7 breast cancer cells, which do not express caveolin-1 and undergo apoptosis. This study delineates for the first time the molecular mechanisms that modulate caveolin-1 gene transcription upon oxidative stress and brings new insights into the redox control of cellular senescence in both normal and cancer cells.

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Section: Introductionmentioning

confidence: 99%

Oxidative Stress Induces Premature Senescence by Stimulating Caveolin-1 Gene Transcription through p38 Mitogen-Activated Protein Kinase/Sp1–Mediated Activation of Two GC-Rich Promoter Elements

et al. 2006

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“…Lipid rafts and caveolae have been known to be involved in different cellular events such as cellular differentiation, immune response, and cell migration. [6][7][8] To find novel lipid raft proteins, and gain new insights for the function of lipid rafts, we along with other groups have identified lipid raft proteins by proteomic analysis. [8][9][10][11][12] Previously, we identified a novel lipid raft protein, a receptor of globular C1q (gC1qR), by the differential proteomic analysis of lipid rafts from 3T3 L1 preadipocytes and adipocytes, and showed that gC1qR is an essential signaling molecule involved in adipogenesis and insulin signal transduction.…”

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TRIM72 negatively regulates myogenesis via targeting insulin receptor substrate-1

et al. 2010

Cell Death Differ

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Lipid rafts have been known to be platforms to initiate cellular signal transduction of insulin-like growth factor (IGF) inducing skeletal muscle differentiation and hypertrophy. Here, tripartite motif 72 (TRIM72), with a really interesting new gene (RING)-finger domain, a B-box, two coiled-coil domains, and a SPRY (SPla and RYanodine receptor) domain, was revealed to be predominantly expressed in the sarcolemma lipid rafts of skeletal and cardiac muscles. Adenoviral TRIM72 overexpression prevented but RNAi-mediated TRIM72 silencing enhanced C2C12 myogenesis by modulating the IGF-induced insulin receptor substrate-1 (IRS-1) activation through the molecular association of TRIM72 with IRS-1. Furthermore, myogenic activity was highly enhanced with increased IGF-induced Akt activation in the satellite cells of TRIM72 À/À mice, compared to those of TRIM72 þ / þ mice. Because TRIM72 promoter analysis shows that two proximal E-boxes in TRIM72 promoter were essential for MyoD-and Akt-dependent TRIM72 transcription, we can conclude that TRIM72 is a novel antagonist of IRS-1, and is essential as a negative regulator of IGF-induced muscle differentiation.

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“…24 In a heterologous cell system, LGMD-1C mutants of Cav-3 behave in a dominant-negative fashion, causing the retention of wild-type Cav-3 at the level of the Golgi complex. 25 Further analysis has demonstrated that LGMD-1C mutants of Cav-3 undergo ubiquitination and proteasomal degradation.…”

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Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

Bonuccelli

Sotgia

Schubert

et al. 2003

The American Journal of Pathology

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Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is absent in the skeletal muscle of DMD patients and mdx mice. At the plasma membrane of skeletal muscle fibers, dystrophin associates with a multimeric protein complex, termed the dystrophin-glycoprotein complex (DGC). Protein members of this complex are normally absent or greatly reduced in dystrophin-deficient skeletal muscle fibers, and are thought to undergo degradation through an unknown pathway. As such, we reasoned that inhibition of the proteasomal degradation pathway might rescue the expression and subcellular localization of dystrophin-associated proteins. To test this hypothesis, we treated mdx mice with the wellcharacterized proteasomal inhibitor MG-132. First, we locally injected MG-132 into the gastrocnemius muscle, and observed the outcome after 24 hours. Next, we performed systemic treatment using an osmotic pump that allowed us to deliver different concentrations of the proteasomal inhibitor, over an 8-day period. By immunofluorescence and Western blot analysis, we show that administration of the proteasomal inhibitor MG-132 effectively rescues the expression levels and plasma membrane localization of dystrophin, ␤-dystroglycan, ␣-dystroglycan, and ␣-sarcoglycan in skeletal muscle fibers from mdx mice. Furthermore, we show that systemic treatment with the proteasomal inhibitor 1) reduces muscle membrane damage, as revealed by vital staining (with Evans blue dye) of the diaphragm and gastrocnemius muscle isolated from treated mdx mice, and 2) ameliorates the histopathological signs of muscular dystrophy, as judged by hematoxylin and eosin staining of muscle biopsies taken from treated mdx mice. Duchenne muscular dystrophy (DMD) is one of the most prevalent and severe inherited diseases of childhood, characterized by progressive muscular wasting and weakness. The deficient gene product, dystrophin, 1 is a peripheral membrane protein of ϳ426 kd, which is expressed in muscle tissues and the brain. At the plasma membrane, dystrophin associates with a large multimeric complex, termed the dystrophin-glycoprotein complex (DGC). 2 The DGC is composed of two subcomplexes: the dystroglycan complex (␣ and ␤ subunits) and the sarcoglycan complex (␣, ␤, ␥, and ␦ subunits). The Nterminal region of dystrophin interacts directly with the cytoskeletal protein actin, while the dystrophin C-terminal domain binds to the plasma membrane through interactions with ␤-dystroglycan. As such, dystrophin is thought

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Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy

Cited by 533 publications

References 26 publications

Oxidative Stress Induces Premature Senescence by Stimulating Caveolin-1 Gene Transcription through p38 Mitogen-Activated Protein Kinase/Sp1–Mediated Activation of Two GC-Rich Promoter Elements

Oxidative Stress Induces Premature Senescence by Stimulating Caveolin-1 Gene Transcription through p38 Mitogen-Activated Protein Kinase/Sp1–Mediated Activation of Two GC-Rich Promoter Elements

TRIM72 negatively regulates myogenesis via targeting insulin receptor substrate-1

Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

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