Protein Tyrosine Kinases, $p56^{lck}\;and\;p59^{fyn}$, MAP Kinase JNK1 Provide an Early Signal Required for Upregulation of Fas Ligand Expression in Aburatubolactam C-Induced Apoptosis of Human Jurkat T Cells

  • BAE MYUNG AE (Laboratory of Immunobiology, Department of Microbiology, College of Natural Sciences, Kyungpook National University, Current address: Laboratory of Molecular Pharmacology and Physiology, Bio-Medicinal Science Division, Korea Research Institute of Chemical Technology) ;
  • JUN DO YOUN (Institute for Genetic Engineering, Kyungpook National University) ;
  • KIM KYUNG MIN (Institute for Genetic Engineering, Kyungpook National University) ;
  • KIM SANG KOOK (Institute for Genetic Engineering, Kyungpook National University) ;
  • CHUN JANG SOO (Department of Life Science, Kwangju Institute of Science and Technology) ;
  • TAUB DENNIS (Laboratory of Immunobiology, Gerontology Research Centerer) ;
  • PARK WAN (Laboratory of Immunobiology, Department of Microbiology, College of Natural Sciences, Kyungpook National University) ;
  • MOON BYUNG-JO (Department of Biochemistry, College of Natural Sciences, Kyungpook National University) ;
  • KIM YOUNG HO (Laboratory of Immunobiology, Department of Microbiology, College of Natural Sciences, Kyungpook National University)
  • Published : 2005.08.01

Abstract

The signaling mechanism underlying aburatubolactam C-induced FasL upregulation was investigated in human Jurkat T cells. After treatment with aburatubolactam C, the src-family PTKs $p56^{lck}\;and\;p59^{fyn}$, and MAP kinases ERK2 and JNK1, were activated prior to FasL upregulation; Both $p56^{lck}\;and\;p59^{fyn}$ were directly activated 2.4- and 2.2-fold, respectively, in vitro by aburatubolactam C. The aburatubolactam C-induced cellular changes, including the activation of ERK2 and INK1, and FasL upregulation, were completely prevented by the PTK inhibitor genistein. The activation of protein kinase C (PKC$\delta,\;\epsilon\;and\;\mu$ was also induced following aburatubolactam C treatment. Although the activation of $p56^{lck}$ and tyrosine phosphorylation of the cellular proteins were not blocked by the PKC inhibitor GFl09203X, the activation of ERK2 was completely abrogated, along with a detectably enhanced JNK1 activation; FasL upregulation, and apoptosis. However, the FasL upregulation and apoptosis were significantly inhibited by the PKC activator PMA, with a remarkable increase in the ERK2 activation. The cytotoxic effect of aburatubolactam C was reduced in the presence of the anti-Fas neutralizing antibody ZB-4. Although ectopic expression of Bcl-2 failed to completely block the cytotoxicity of aburatubolactam C, it was clearly suppressed. The c-Fos mRNA expression was upregulated in a biphasic manner, where the second phasic expression overlapped with the FasL upregulation. Accordingly, these results demonstrate that aburatubolactam C-induced apoptosis is exerted, at least in part, by FasL upregulation dictated by activation of the PTK ($p56^{lck}\;and\;p59^{fyn}$) /JNKI pathway, which is negatively affected by the concurrent activation of the PKC/ERK2 pathway proximal to PTK activation.

Keywords

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