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

Publication ,  Journal Article
Husain, M; Meggs, LG; Vashistha, H; Simoes, S; Griffiths, KO; Kumar, D; Mikulak, J; Mathieson, PW; Saleem, MA; Del Valle, L; Pina-Oviedo, S ...
Published in: J Biol Chem
June 12, 2009

Glomerular 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 (micro-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 micro-36/NL4-3/CIDHP but increased in NL4-3/CIDHP. Acute knockdown of Foxo3a by small interfering RNA induced a 50% increase in micro-36/NL4-3/CIDHP apoptosis, indicating that Foxo3a-dependent responses promote the survival phenotype in micro-36 cells. We conclude that inhibition of p66ShcA redox activity prevents generation of HIV-1 stress signals and activation of the CIDHP apoptosis program.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

June 12, 2009

Volume

284

Issue

24

Start / End Page

16648 / 16658

Location

United States

Related Subject Headings

  • Transfection
  • Threonine
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Shc Signaling Adaptor Proteins
  • Reactive Oxygen Species
  • RNA, Small Interfering
  • Podocytes
  • Phosphorylation
  • Phenotype
  • Oxidative Stress
 

Citation

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Husain, M., Meggs, L. G., Vashistha, H., Simoes, S., Griffiths, K. O., Kumar, D., … Singhal, P. C. (2009). Inhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis. J Biol Chem, 284(24), 16648–16658. https://doi.org/10.1074/jbc.M109.008482
Husain, Mohammad, Leonard G. Meggs, Himanshu Vashistha, Sonia Simoes, Kevin O. Griffiths, Dileep Kumar, Joanna Mikulak, et al. “Inhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis.J Biol Chem 284, no. 24 (June 12, 2009): 16648–58. https://doi.org/10.1074/jbc.M109.008482.
Husain M, Meggs LG, Vashistha H, Simoes S, Griffiths KO, Kumar D, et al. Inhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis. J Biol Chem. 2009 Jun 12;284(24):16648–58.
Husain, Mohammad, et al. “Inhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis.J Biol Chem, vol. 284, no. 24, June 2009, pp. 16648–58. Pubmed, doi:10.1074/jbc.M109.008482.
Husain M, Meggs LG, Vashistha H, Simoes S, Griffiths KO, Kumar D, Mikulak J, Mathieson PW, Saleem MA, Del Valle L, Pina-Oviedo S, Wang JY, Seshan SV, Malhotra A, Reiss K, Singhal PC. Inhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis. J Biol Chem. 2009 Jun 12;284(24):16648–16658.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

June 12, 2009

Volume

284

Issue

24

Start / End Page

16648 / 16658

Location

United States

Related Subject Headings

  • Transfection
  • Threonine
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Shc Signaling Adaptor Proteins
  • Reactive Oxygen Species
  • RNA, Small Interfering
  • Podocytes
  • Phosphorylation
  • Phenotype
  • Oxidative Stress