Protein kinase Cε regulates tumor necrosis factor-α-induced stannin gene expression

Brian E. Reese, Collin Davidson, Melvin L. Billingsley, Jong Yun

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Stannin (Snn) is a highly conserved vertebrate protein that has been closely linked to trimethyltin (TMT) toxicity. We have previously demonstrated that Snn is required for TMT-induced cell death. Others have shown that TMT exposure results in tumor necrosis factor-α (TNFα) production and that TNFα treatment induces Snn gene expression in human umbilical vein endothelial cells (HUVECs). In this study, we investigated a signaling mechanism by which Snn gene expression is regulated by TMT and demonstrated that TNFα stimulates Snn gene expression in a protein kinase Cε-dependent manner in HUVECs in response to TMT exposure. Supporting this, we show that TMT-induced toxicity is significantly blocked by pretreatment with an anti-TNFα antibody in HUVECs. Using a quantitative real-time polymerase chain reaction assay, we also show that the level of Snn gene expression is significantly increased in HUVECs in response to either TMT or TNFα-treatment. This TNFα-induced Snn gene expression is blocked when HUVECs were pretreated with bisindolylmaleimide I, an inhibitor of protein kinase C (PKC). In contrast, when HUVECs were treated with phorbol 12-myristate 13-acetate, a PKC activator, we observed a significant increase in Snn gene expression. Using isotypespecific siRNA against PKC, we further show that knockdown of PKCε, but not PKCδ or PKCζ, significantly blocked TNFα-induced Snn gene expression. Together, these results indicate that TNFα-induced, PKCε-dependent Snn expression may be a critical factor in TMT-induced cytotoxicity.

Original languageEnglish (US)
Pages (from-to)61-69
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume314
Issue number1
DOIs
StatePublished - Jul 2005

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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