
<ArticleTitle>HIV <prot>Tat</prot> activates <prot>c-Jun</prot> amino-terminal kinase through an oxidant-dependent mechanism.</ArticleTitle>
<AbstractText>The HIV-1 accessory protein <prot>Tat</prot> has been found to exert profound effects on vascular cell behavior. Recently, <prot>Tat</prot> has been found to activate the <prot><prot>c-Jun</prot> amino-terminal kinase</prot> (<prot>JNK1</prot>, <prot>SAPK</prot>) MAP kinase in lymphoid cells. We found that purified <prot>Tat</prot> rapidly activated <prot>JNK1</prot> in human umbilical vein endothelial cells and ECV-304 cells, and coculture of ECV-304 cells with <prot>Tat</prot>-transfected HeLa cells resulted in persistent activation of <prot>JNK1</prot>. In addition, lower doses of <prot>Tat</prot> potentiated <prot>TNFalpha</prot>-induced <prot>JNK1</prot> activation, although higher doses paradoxically diminished <prot>JNK1</prot> activation by <prot>TNFalpha</prot>. Treatment of ECV-304 cells with <prot>Tat</prot> acutely increased intracellular oxidant levels, and <prot>Tat</prot>-induced oxidant activity was decreased by two structurally distinct NADPH oxidase inhibitors, diphenylene iodonium and apocynin. Both oxidase inhibitors and the thiol antioxidant N-acetyl cysteine decreased <prot>Tat</prot>-induced <prot>JNK1</prot> activation in parallel with reduction in oxidant levels. Activation of <prot>JNK1</prot> by <prot>Tat</prot> was also inhibited by cytochalasin B, suggesting that <prot>Tat</prot> signaling was dependent upon intact cytoskeletal function. Indeed, <prot>JNK1</prot> activation by <prot>Tat</prot> was associated with <prot>actin</prot> microfilament rearrangement. We conclude that HIV <prot>Tat</prot> may cause acute and persistent activation of the JNK MAP kinase through activation of a specific oxidase.</AbstractText>
