PubMed:28468941 JSON TXT

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LitCoin-entities-OrganismTaxon-PD

{"project":"LitCoin-entities-OrganismTaxon-PD","denotations":[{"id":"T1","span":{"begin":775,"end":780},"obj":"OrganismTaxon"}],"attributes":[{"id":"A1","pred":"db_id","subj":"T1","obj":"NCBItxid:10090"},{"id":"A2","pred":"db_id","subj":"T1","obj":"NCBItxid:10088"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-sentences

{"project":"LitCoin-sentences","denotations":[{"id":"T1","span":{"begin":0,"end":215},"obj":"Sentence"},{"id":"T2","span":{"begin":216,"end":346},"obj":"Sentence"},{"id":"T3","span":{"begin":347,"end":513},"obj":"Sentence"},{"id":"T4","span":{"begin":514,"end":610},"obj":"Sentence"},{"id":"T5","span":{"begin":611,"end":722},"obj":"Sentence"},{"id":"T6","span":{"begin":723,"end":901},"obj":"Sentence"},{"id":"T7","span":{"begin":902,"end":1010},"obj":"Sentence"},{"id":"T8","span":{"begin":1011,"end":1154},"obj":"Sentence"},{"id":"T9","span":{"begin":1155,"end":1223},"obj":"Sentence"},{"id":"T10","span":{"begin":1224,"end":1377},"obj":"Sentence"},{"id":"T11","span":{"begin":1378,"end":1706},"obj":"Sentence"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-entities

LitCoin_Mondo

{"project":"LitCoin_Mondo","denotations":[{"id":"T1","span":{"begin":192,"end":214},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":298,"end":339},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":308,"end":339},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A3","pred":"mondo_id","subj":"T3","obj":"0015924"},{"id":"A1","pred":"mondo_id","subj":"T1","obj":"0005149"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"0017148"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-SeqVar

{"project":"LitCoin-SeqVar","denotations":[{"id":"T1","span":{"begin":119,"end":128},"obj":"SequenceVariant"},{"id":"T2","span":{"begin":242,"end":251},"obj":"SequenceVariant"},{"id":"T3","span":{"begin":681,"end":690},"obj":"SequenceVariant"},{"id":"T4","span":{"begin":1355,"end":1364},"obj":"SequenceVariant"},{"id":"T5","span":{"begin":1687,"end":1696},"obj":"SequenceVariant"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-GeneOrGeneProduct-v0

LitCoin-GeneOrGeneProduct-v2

{"project":"LitCoin-GeneOrGeneProduct-v2","denotations":[{"id":"T1","span":{"begin":9,"end":19},"obj":"GeneOrGeneProduct"},{"id":"T2","span":{"begin":29,"end":33},"obj":"GeneOrGeneProduct"},{"id":"T3","span":{"begin":202,"end":214},"obj":"GeneOrGeneProduct"},{"id":"T4","span":{"begin":231,"end":241},"obj":"GeneOrGeneProduct"},{"id":"T5","span":{"begin":327,"end":339},"obj":"GeneOrGeneProduct"},{"id":"T6","span":{"begin":383,"end":401},"obj":"GeneOrGeneProduct"},{"id":"T7","span":{"begin":483,"end":494},"obj":"GeneOrGeneProduct"},{"id":"T8","span":{"begin":504,"end":512},"obj":"GeneOrGeneProduct"},{"id":"T9","span":{"begin":555,"end":565},"obj":"GeneOrGeneProduct"},{"id":"T10","span":{"begin":745,"end":755},"obj":"GeneOrGeneProduct"},{"id":"T11","span":{"begin":759,"end":769},"obj":"GeneOrGeneProduct"},{"id":"T12","span":{"begin":770,"end":774},"obj":"GeneOrGeneProduct"},{"id":"T13","span":{"begin":864,"end":871},"obj":"GeneOrGeneProduct"},{"id":"T14","span":{"begin":879,"end":900},"obj":"GeneOrGeneProduct"},{"id":"T15","span":{"begin":937,"end":947},"obj":"GeneOrGeneProduct"},{"id":"T16","span":{"begin":961,"end":971},"obj":"GeneOrGeneProduct"},{"id":"T17","span":{"begin":1144,"end":1151},"obj":"GeneOrGeneProduct"},{"id":"T18","span":{"begin":1212,"end":1222},"obj":"GeneOrGeneProduct"},{"id":"T19","span":{"begin":1238,"end":1244},"obj":"GeneOrGeneProduct"},{"id":"T20","span":{"begin":1260,"end":1264},"obj":"GeneOrGeneProduct"},{"id":"T21","span":{"begin":1306,"end":1313},"obj":"GeneOrGeneProduct"},{"id":"T22","span":{"begin":1316,"end":1323},"obj":"GeneOrGeneProduct"},{"id":"T23","span":{"begin":1438,"end":1449},"obj":"GeneOrGeneProduct"},{"id":"T24","span":{"begin":1453,"end":1463},"obj":"GeneOrGeneProduct"},{"id":"T25","span":{"begin":1516,"end":1520},"obj":"GeneOrGeneProduct"},{"id":"T26","span":{"begin":1558,"end":1562},"obj":"GeneOrGeneProduct"},{"id":"T27","span":{"begin":1676,"end":1686},"obj":"GeneOrGeneProduct"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-Disease-MeSH

{"project":"LitCoin-Disease-MeSH","denotations":[{"id":"T1","span":{"begin":192,"end":214},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":298,"end":339},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":341,"end":344},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T4","span":{"begin":1655,"end":1658},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A2","pred":"originalLabel","subj":"T2","obj":"D065627"},{"id":"A1","pred":"originalLabel","subj":"T1","obj":"D006976"},{"id":"A4","pred":"originalLabel","subj":"T4","obj":"D000081029"},{"id":"A3","pred":"originalLabel","subj":"T3","obj":"D000081029"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-GeneOrGeneProduct-v3

{"project":"LitCoin-GeneOrGeneProduct-v3","denotations":[{"id":"T1","span":{"begin":9,"end":19},"obj":"GeneOrGeneProduct"},{"id":"T2","span":{"begin":29,"end":33},"obj":"GeneOrGeneProduct"},{"id":"T3","span":{"begin":231,"end":241},"obj":"GeneOrGeneProduct"},{"id":"T4","span":{"begin":383,"end":401},"obj":"GeneOrGeneProduct"},{"id":"T5","span":{"begin":555,"end":565},"obj":"GeneOrGeneProduct"},{"id":"T6","span":{"begin":745,"end":755},"obj":"GeneOrGeneProduct"},{"id":"T7","span":{"begin":759,"end":769},"obj":"GeneOrGeneProduct"},{"id":"T8","span":{"begin":937,"end":947},"obj":"GeneOrGeneProduct"},{"id":"T9","span":{"begin":961,"end":971},"obj":"GeneOrGeneProduct"},{"id":"T10","span":{"begin":1144,"end":1151},"obj":"GeneOrGeneProduct"},{"id":"T11","span":{"begin":1212,"end":1222},"obj":"GeneOrGeneProduct"},{"id":"T12","span":{"begin":1260,"end":1264},"obj":"GeneOrGeneProduct"},{"id":"T13","span":{"begin":1306,"end":1313},"obj":"GeneOrGeneProduct"},{"id":"T14","span":{"begin":1453,"end":1463},"obj":"GeneOrGeneProduct"},{"id":"T15","span":{"begin":1516,"end":1520},"obj":"GeneOrGeneProduct"},{"id":"T16","span":{"begin":1558,"end":1562},"obj":"GeneOrGeneProduct"},{"id":"T17","span":{"begin":1676,"end":1686},"obj":"GeneOrGeneProduct"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin_Mondo_095

{"project":"LitCoin_Mondo_095","denotations":[{"id":"T1","span":{"begin":192,"end":214},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":298,"end":339},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":341,"end":344},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T5","span":{"begin":1655,"end":1658},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A5","pred":"mondo_id","subj":"T5","obj":"0015924"},{"id":"A6","pred":"mondo_id","subj":"T5","obj":"0024533"},{"id":"A3","pred":"mondo_id","subj":"T3","obj":"0015924"},{"id":"A4","pred":"mondo_id","subj":"T3","obj":"0024533"},{"id":"A1","pred":"mondo_id","subj":"T1","obj":"0005149"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"0017148"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-MeSH-Disease-2

{"project":"LitCoin-MeSH-Disease-2","denotations":[{"id":"T1","span":{"begin":192,"end":214},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":298,"end":339},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":341,"end":344},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T4","span":{"begin":1655,"end":1658},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"ID:","subj":"T1","obj":"D006976"},{"id":"A4","pred":"ID:","subj":"T4","obj":"D000081029"},{"id":"A2","pred":"ID:","subj":"T2","obj":"D065627"},{"id":"A3","pred":"ID:","subj":"T3","obj":"D000081029"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-MONDO_bioort2019

{"project":"LitCoin-MONDO_bioort2019","denotations":[{"id":"T1","span":{"begin":192,"end":214},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":298,"end":339},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":341,"end":344},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T4","span":{"begin":1655,"end":1658},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"#label","subj":"T1","obj":"D006976"},{"id":"A3","pred":"#label","subj":"T3","obj":"D000081029"},{"id":"A2","pred":"#label","subj":"T2","obj":"D065627"},{"id":"A4","pred":"#label","subj":"T4","obj":"D000081029"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-Chemical-MeSH-CHEBI

{"project":"LitCoin-Chemical-MeSH-CHEBI","denotations":[{"id":"T1","span":{"begin":88,"end":95},"obj":"ChemicalEntity"},{"id":"T3","span":{"begin":341,"end":344},"obj":"ChemicalEntity"},{"id":"T7","span":{"begin":1655,"end":1658},"obj":"ChemicalEntity"}],"attributes":[{"id":"A1","pred":"ID:","subj":"T1","obj":"D000225"},{"id":"A2","pred":"ID:","subj":"T1","obj":"http://purl.obolibrary.org/obo/CHEBI_16708"},{"id":"A3","pred":"ID:","subj":"T3","obj":"http://purl.obolibrary.org/obo/CHEBI_53305"},{"id":"A4","pred":"ID:","subj":"T3","obj":"http://purl.obolibrary.org/obo/CHEBI_33848"},{"id":"A5","pred":"ID:","subj":"T3","obj":"http://purl.obolibrary.org/obo/CHEBI_31204"},{"id":"A6","pred":"ID:","subj":"T3","obj":"http://purl.obolibrary.org/obo/CHEBI_104011"},{"id":"A7","pred":"ID:","subj":"T7","obj":"http://purl.obolibrary.org/obo/CHEBI_53305"},{"id":"A8","pred":"ID:","subj":"T7","obj":"http://purl.obolibrary.org/obo/CHEBI_33848"},{"id":"A9","pred":"ID:","subj":"T7","obj":"http://purl.obolibrary.org/obo/CHEBI_31204"},{"id":"A10","pred":"ID:","subj":"T7","obj":"http://purl.obolibrary.org/obo/CHEBI_104011"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-NCBITaxon-2

{"project":"LitCoin-NCBITaxon-2","denotations":[{"id":"T1","span":{"begin":133,"end":140},"obj":"OrganismTaxon"},{"id":"T2","span":{"begin":582,"end":589},"obj":"OrganismTaxon"},{"id":"T3","span":{"begin":775,"end":780},"obj":"OrganismTaxon"},{"id":"T4","span":{"begin":1662,"end":1670},"obj":"OrganismTaxon"}],"text":"Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.\nA heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation."}

LitCoin-training-merged