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Article: Inhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis

TitleInhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis
Authors
Issue Date2009
Citation
Journal of Biological Chemistry, 2009, v. 284 n. 24, p. 16648-16658 How to Cite?
AbstractGlomerular visceral epithelial cells (podocytes) play a critical role in the pathogenesis of human immunodeficiency virus (HIV)-associated nephropathy. A key question concerns the mechanism(s) by which the HIV-1 genome alters the phenotype of the highly specialized, terminally differentiated podocytes. Here, using an in vitro system of conditionally immortalized differentiated human podocytes (CIDHPs), we document a pivotal role for the p66ShcA protein in HIV-1-induced reactive oxygen species generation and CIDHP apoptosis. CIDHP transfected with truncated HIV-1 construct (NL4-3) exhibit increased reactive oxygen species metabolism, DNA strand breaks, and a 5-fold increase in apoptosis, whereas the opposite was true for NL4-3/CIDHP co-transfected with mu-36p66ShcA (mu-36) dominant negative expression vector or isoform-specific p66-small interfering RNA. Phosphorylation at Ser-36 of the wild type p66ShcA protein, required for p66ShcA redox function and inhibition of the potent stress response regulator Foxo3a, was unchanged in mu-36/NL4-3/CIDHP but increased in NL4-3/CIDHP. Acute knockdown of Foxo3a by small interfering RNA induced a 50% increase in mu-36/NL4-3/CIDHP apoptosis, indicating that Foxo3a-dependent responses promote the survival phenotype in mu-36 cells.Weconclude that inhibition of p66ShcA redox activity prevents generation of HIV-1 stress signals and activation of the CIDHP apoptosis program. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/195474
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHusain, M-
dc.contributor.authorMeggs, LG-
dc.contributor.authorVashistha, H-
dc.contributor.authorSimoes, S-
dc.contributor.authorGriffiths, KO-
dc.contributor.authorKumar, D-
dc.contributor.authorMikulak, J-
dc.contributor.authorMathieson, PW-
dc.contributor.authorSaleem, MA-
dc.contributor.authorDel Valle, L-
dc.contributor.authorPina-Oviedo, S-
dc.contributor.authorWang, JY-
dc.contributor.authorSeshan, SV-
dc.contributor.authorMalhotra, A-
dc.contributor.authorReiss, K-
dc.contributor.authorSinghal, PC-
dc.date.accessioned2014-02-28T06:12:13Z-
dc.date.available2014-02-28T06:12:13Z-
dc.date.issued2009-
dc.identifier.citationJournal of Biological Chemistry, 2009, v. 284 n. 24, p. 16648-16658-
dc.identifier.issn0021-9258-
dc.identifier.urihttp://hdl.handle.net/10722/195474-
dc.description.abstractGlomerular visceral epithelial cells (podocytes) play a critical role in the pathogenesis of human immunodeficiency virus (HIV)-associated nephropathy. A key question concerns the mechanism(s) by which the HIV-1 genome alters the phenotype of the highly specialized, terminally differentiated podocytes. Here, using an in vitro system of conditionally immortalized differentiated human podocytes (CIDHPs), we document a pivotal role for the p66ShcA protein in HIV-1-induced reactive oxygen species generation and CIDHP apoptosis. CIDHP transfected with truncated HIV-1 construct (NL4-3) exhibit increased reactive oxygen species metabolism, DNA strand breaks, and a 5-fold increase in apoptosis, whereas the opposite was true for NL4-3/CIDHP co-transfected with mu-36p66ShcA (mu-36) dominant negative expression vector or isoform-specific p66-small interfering RNA. Phosphorylation at Ser-36 of the wild type p66ShcA protein, required for p66ShcA redox function and inhibition of the potent stress response regulator Foxo3a, was unchanged in mu-36/NL4-3/CIDHP but increased in NL4-3/CIDHP. Acute knockdown of Foxo3a by small interfering RNA induced a 50% increase in mu-36/NL4-3/CIDHP apoptosis, indicating that Foxo3a-dependent responses promote the survival phenotype in mu-36 cells.Weconclude that inhibition of p66ShcA redox activity prevents generation of HIV-1 stress signals and activation of the CIDHP apoptosis program. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.-
dc.languageeng-
dc.relation.ispartofJournal of Biological Chemistry-
dc.titleInhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1074/jbc.M109.008482-
dc.identifier.pmid19383602-
dc.identifier.scopuseid_2-s2.0-67650236778-
dc.identifier.volume284-
dc.identifier.issue24-
dc.identifier.spage16648-
dc.identifier.epage16658-
dc.identifier.isiWOS:000266730900060-

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