{"corpus_id":19285940,"paper_sha":"ade6e1a61258ca4473eca256c4f7781209f09134","doi":"10.1159/000373989","arxiv_id":null,"pmid":25832774,"pmcid":"PMC4391077","mag_id":1585035603,"dblp_id":null,"acl_id":null,"title":"Enhanced Epithelial-to-Mesenchymal Transition Associated with Lysosome Dysfunction in Podocytes: Role of p62/Sequestosome 1 as a Signaling Hub","year":2015,"publication_date":"2015-03-26","venue":"Cellular Physiology and Biochemistry","journal":{"name":"Cellular Physiology and Biochemistry","pages":"1773 - 1786","volume":"35"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, N.I.H., Extramural"],"s2_fields_of_study":["Biology","Medicine","Chemistry"],"reference_count":86,"citation_count":47,"influential_citation_count":1,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Actins","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D000199"},{"d":"Adaptor Proteins, Signal Transducing","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D048868"},{"d":"CDC2 Protein Kinase","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D016203"},{"d":"Cadherins","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D015820"},{"d":"Cell Differentiation","mj":false,"ui":"D002454"},{"d":"Cell Line","mj":false,"ui":"D002460"},{"d":"Epithelial-Mesenchymal Transition","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"}],"ui":"D058750"},{"d":"Humans","mj":false,"ui":"D006801"},{"d":"Lysosomes","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D008247"},{"d":"Macrolides","mj":false,"qs":[{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D018942"},{"d":"Microscopy, Confocal","mj":false,"ui":"D018613"},{"d":"Mitosis","mj":false,"ui":"D008938"},{"d":"NF-E2-Related Factor 2","mj":false,"qs":[{"q":"antagonists & inhibitors","mj":false,"ui":"Q000037"},{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D051267"},{"d":"NF-kappa B","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D016328"},{"d":"Podocytes","mj":false,"qs":[{"q":"cytology","mj":false,"ui":"Q000166"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D050199"},{"d":"RNA Interference","mj":false,"ui":"D034622"},{"d":"RNA, Small Interfering","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D034741"},{"d":"Sequestosome-1 Protein","mj":false,"ui":"D000071456"},{"d":"Signal Transduction","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"}],"ui":"D015398"},{"d":"Vacuolar Proton-Translocating ATPases","mj":false,"qs":[{"q":"antagonists & inhibitors","mj":false,"ui":"Q000037"},{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D025262"},{"d":"Zonula Occludens-1 Protein","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D062826"}],"chemicals":[{"n":"ACTA2 protein, human","ui":"C541116","reg":"0"},{"n":"Actins","ui":"D000199","reg":"0"},{"n":"Adaptor Proteins, Signal Transducing","ui":"D048868","reg":"0"},{"n":"Cadherins","ui":"D015820","reg":"0"},{"n":"Macrolides","ui":"D018942","reg":"0"},{"n":"NF-E2-Related Factor 2","ui":"D051267","reg":"0"},{"n":"NF-kappa B","ui":"D016328","reg":"0"},{"n":"NFE2L2 protein, human","ui":"C495635","reg":"0"},{"n":"RNA, Small Interfering","ui":"D034741","reg":"0"},{"n":"SQSTM1 protein, human","ui":"C099718","reg":"0"},{"n":"Sequestosome-1 Protein","ui":"D000071456","reg":"0"},{"n":"TJP1 protein, human","ui":"C569042","reg":"0"},{"n":"Zonula Occludens-1 Protein","ui":"D062826","reg":"0"},{"n":"bafilomycin A","ui":"C057620","reg":"116764-51-3"},{"n":"CDC2 Protein Kinase","ui":"D016203","reg":"EC 2.7.11.22"},{"n":"Vacuolar Proton-Translocating ATPases","ui":"D025262","reg":"EC 3.6.1.-"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://karger.com/cpb/article-pdf/35/5/1773/2431474/000373989.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/ade6e1a61258ca4473eca256c4f7781209f09134","s2_open_access_license":"CCBYNC","s2_open_access_status":"GOLD","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Background: Autophagy is of importance in the regulation of cell differentiation and senescence in podocytes. It is possible that derangement of autophagy under different pathological conditions activates or enhances Epithelial-to-Mesenchymal Transition (EMT) in podocytes, resulting in glomerular sclerosis. To test this hypothesis, the present study produced lysosome dysfunction by inhibition of the vacuolar H+-ATPase (V-ATPase) to test whether deficiency of autophagic flux leads to enhancement of EMT in podocytes. Methods and Results: By Western blot and confocal analysis, lysosome inhibition using a V-ATPase inhibitor or its siRNA was found to markedly decreases the epithelial markers (P-cadherin and ZO-1) and increases the mesenchymal markers (FSP-1 and α-SMA). This enhancement was accompanied by deficient autophagic flux, as demonstrated by marked increases in LC3B-II and p62/Sequestosome 1. However, inhibition of autophagosome formation using spaudin-1 significantly attenuated both enhancement of EMT and deficiency of autophagic flux. To explore the mechanisms by which deficient autophagic flux enhances EMT, we tested the role of accumulated p62 as a signal hub in this process. Neither the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear kappa-light-chain-enhancer pathways of p62 contributed to enhanced EMT. However, inhibition of cyclin-dependent kinase 1 (CDK1) activity reduced the phosphorylation of p62 and enhanced EMT in podocytes similar to lysosome dysfunction. Conclusion: The lack of phosphorylated p62 leads to a faster exit from cell mitosis, enhanced EMT associated with lysosome dysfunction may be attributed to accumulation of p62 and associated reduction of p62 phosphorylation.","claims":[{"public_id":"cl_438058c7a5a4b8177050e3deda64d6bb","status":"active","text":"Accumulated p62 contributes to the signaling changes linked to lysosome dysfunction, while the Nrf2 and NF-κB pathways do not contribute to the enhanced epithelial-to-mesenchymal transition.","confidence":0.89,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_438058c7a5a4b8177050e3deda64d6bb"},{"public_id":"cl_cd2092871927dafe1c29618e769b3d5e","status":"active","text":"Blocking autophagosome formation with spautin-1 attenuates both the epithelial-to-mesenchymal transition enhancement and the autophagic flux deficiency.","confidence":0.91,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_cd2092871927dafe1c29618e769b3d5e"},{"public_id":"cl_cc8a0ffa5d149c9286518ac90c129979","status":"active","text":"Deficient autophagic flux accompanies the enhanced epithelial-to-mesenchymal transition, as shown by increased LC3B-II and p62/Sequestosome 1.","confidence":0.95,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_cc8a0ffa5d149c9286518ac90c129979"},{"public_id":"cl_1be2936bdbdd97d284378089302e4025","status":"active","text":"Lysosome dysfunction induced by V-ATPase inhibition or V-ATPase siRNA markedly decreases epithelial markers and increases mesenchymal markers in podocytes.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_1be2936bdbdd97d284378089302e4025"},{"public_id":"cl_54ea8af546cfbfa52b5c9ed3c7dbe470","status":"active","text":"Reduced CDK1 activity lowers p62 phosphorylation and produces an epithelial-to-mesenchymal transition phenotype similar to that caused by lysosome dysfunction.","confidence":0.93,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_54ea8af546cfbfa52b5c9ed3c7dbe470"}],"concepts":[{"public_id":"co_17b126f439ad97b175d04548612d06b0","status":"active","name":"autophagic flux","description":"The dynamic process of autophagosome formation, maturation, and degradation through lysosomes.","types":["cellular 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