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TOXICOLOGY

Protein Kinase C Regulates Tumor Necrosis Factor--Induced Stannin Gene Expression

Department of Pharmacology (B.E.R., C.D., M.L.B., J.Y.) and Jake Gittlen Cancer Research Institute (J.Y.), Penn State College of Medicine, Hershey, Pennsylvania

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- (TNF) production and that TNF 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 TNF stimulates Snn gene expression in a protein kinase C-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-TNF 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 TNF treatment. This TNF-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 isotype-specific siRNA against PKC, we further show that knockdown of PKC, but not PKC or PKC, significantly blocked TNF-induced Snn gene expression. Together, these results indicate that TNF-induced, PKC-dependent Snn expression may be a critical factor in TMT-induced cytotoxicity.

Address correspondence to: Melvin Billingsley, Department of Pharmacology H078, 500 University Drive, Hershey, PA 17033. E-mail address: mlb8{at}psu.edu