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Article: Activation of autophagy of aggregation-prone ubiquitinated proteins by timosaponin A-III

TitleActivation of autophagy of aggregation-prone ubiquitinated proteins by timosaponin A-III
Authors
Issue Date2011
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal of Biological Chemistry, 2011, v. 286 n. 36, p. 31684-31696 How to Cite?
AbstractChemical modulators of autophagy provide useful pharmacological tools for examination of autophagic processes, and also may lead to new therapeutic agents for diseases in which control of cellular sequestration and degradation capacity are beneficial. We have identified that timosaponin A-III (TAIII), a medicinal saponin reported to exhibit anticancer properties and improve brain function, is a pronounced activator of autophagy. In this work, the salient features and functional role of TAIII-induced autophagy were investigated. In TAIII-treated cells, autophagic flux with increased formation of autophagosomes and conversion into autolysosomes is induced in association with inhibition of mammalian target of rapamycin activity and elevation of cytosolic free calcium. The TAIII-induced autophagy is distinct from conventional induction by rapamycin, exhibiting large autophagic vacuoles that appear to contain significant contents of endosomal membranes and multivesicular bodies. Furthermore, TAIII stimulates biosynthesis of cholesterol, which is incorporated to the autophagic vacuole membranes. The TAIII-induced autophagic vacuoles capture ubiquitinated proteins, and in proteasome-inhibited cells TAIII promotes autophagy of aggregation-prone ubiquitinated proteins. Our studies demonstrate that TAIII induced a distinct form of autophagy, and one of its pharmacological actions is likely to enhance the cellular quality control capacity via autophagic clearance of otherwise accumulated ubiquitinated protein aggregates.
Persistent Identifierhttp://hdl.handle.net/10722/168560
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLok, CNen_US
dc.contributor.authorSy, LKen_US
dc.contributor.authorLiu, Fen_US
dc.contributor.authorChe, CMen_US
dc.date.accessioned2012-10-08T03:20:41Z-
dc.date.available2012-10-08T03:20:41Z-
dc.date.issued2011en_US
dc.identifier.citationJournal of Biological Chemistry, 2011, v. 286 n. 36, p. 31684-31696en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/168560-
dc.description.abstractChemical modulators of autophagy provide useful pharmacological tools for examination of autophagic processes, and also may lead to new therapeutic agents for diseases in which control of cellular sequestration and degradation capacity are beneficial. We have identified that timosaponin A-III (TAIII), a medicinal saponin reported to exhibit anticancer properties and improve brain function, is a pronounced activator of autophagy. In this work, the salient features and functional role of TAIII-induced autophagy were investigated. In TAIII-treated cells, autophagic flux with increased formation of autophagosomes and conversion into autolysosomes is induced in association with inhibition of mammalian target of rapamycin activity and elevation of cytosolic free calcium. The TAIII-induced autophagy is distinct from conventional induction by rapamycin, exhibiting large autophagic vacuoles that appear to contain significant contents of endosomal membranes and multivesicular bodies. Furthermore, TAIII stimulates biosynthesis of cholesterol, which is incorporated to the autophagic vacuole membranes. The TAIII-induced autophagic vacuoles capture ubiquitinated proteins, and in proteasome-inhibited cells TAIII promotes autophagy of aggregation-prone ubiquitinated proteins. Our studies demonstrate that TAIII induced a distinct form of autophagy, and one of its pharmacological actions is likely to enhance the cellular quality control capacity via autophagic clearance of otherwise accumulated ubiquitinated protein aggregates.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.rightsJournal of Biological Chemistry. Copyright © American Society for Biochemistry and Molecular Biology, Inc.-
dc.rightseid_2-s2.0-80052408968-
dc.subject.meshAutophagy - drug effectsen_US
dc.subject.meshHeLa Cellsen_US
dc.subject.meshSaponins - pharmacologyen_US
dc.subject.meshSteroids - pharmacologyen_US
dc.subject.meshUbiquitinated Proteins - metabolismen_US
dc.titleActivation of autophagy of aggregation-prone ubiquitinated proteins by timosaponin A-IIIen_US
dc.typeArticleen_US
dc.identifier.emailLok, CN: cnlok@hku.hken_US
dc.identifier.emailSy, LK: sylk@hku.hken_US
dc.identifier.emailLiu, F: chlfl@hku.hken_US
dc.identifier.emailChe, CM: cmche@hku.hk-
dc.identifier.authorityLok, CN=rp00752en_US
dc.identifier.authoritySy, LK=rp00784en_US
dc.identifier.authorityChe, CM=rp00670en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1074/jbc.M110.202531en_US
dc.identifier.pmid21757721-
dc.identifier.pmcidPMC3173142-
dc.identifier.scopuseid_2-s2.0-80052408968en_US
dc.identifier.hkuros205226-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80052408968&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume286en_US
dc.identifier.issue36en_US
dc.identifier.spage31684en_US
dc.identifier.epage31696en_US
dc.identifier.isiWOS:000294487500061-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridChe, CM=7102442791en_US
dc.identifier.scopusauthoridLiu, F=51261061400en_US
dc.identifier.scopusauthoridSy, LK=35874602700en_US
dc.identifier.scopusauthoridLok, CN=7006410829en_US

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