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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >712-Dimethylbenzaanthracene activates protein-tyrosine kinases Fyn and Lck in the HPB-ALL human T-cell line and increases tyrosine phosphorylation of phospholipase C-gamma 1 formation of inositol 145-trisphosphate and mobilization of intracellular calcium.
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712-Dimethylbenzaanthracene activates protein-tyrosine kinases Fyn and Lck in the HPB-ALL human T-cell line and increases tyrosine phosphorylation of phospholipase C-gamma 1 formation of inositol 145-trisphosphate and mobilization of intracellular calcium.

机译：712-二甲基苯并a蒽激活HPB-ALL人T细胞系中的蛋白酪氨酸激酶Fyn和Lck并增加磷脂酶C-γ1的酪氨酸磷酸化形成肌醇145-三磷酸和动员细胞内钙。

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Previous studies have shown that the immunosuppressive and carcinogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA) impairs Ca(2+)-dependent transmembrane signaling in human and murine lymphocytes. The purpose of the present studies was to analyze potential mechanisms of immunosuppression by DMBA and to examine effects on Ca2+ homeostasis and antigen-receptor signaling in human T cells. DMBA produced a rapid and sustained increase in Ca2+ levels in HPB-ALL cells by release of cytoplasmic Ca2+. DMBA also inhibited anti-CD3/CD4 mobilization of Ca2+ in HPB-ALL cells, with half-maximal inhibition occurring at approximately 4 hr. Thus, the kinetics for initial Ca2+ mobilization and inhibition of the anti-CD3/CD4 response differed. The rapid rise in intracellular Ca2+ induced by DMBA alone was accompanied by a rapid but transient increase in inositol 1,4,5-trisphosphate and tyrosine phosphorylation of phospholipase C-gamma 1. The pattern of tyrosine phosphorylation induced by DMBA in HPB-ALL cells was remarkably similar to that induced by anti-CD3/CD4 activation. Thus, DMBA-induced phosphorylation may mimic antigen-receptor activation in T cells, which may lead to alterations in antigen responsiveness. The mechanism of DMBA-induced tyrosine phosphorylation of phospholipase C-gamma 1 may have been due to an increase in protein-tyrosine kinase activity, since it was found that DMBA produced a > 2-fold increase in the activity of the T-cell receptor-associated Src-family kinases Fyn and Lck. The kinetics of activation of protein-tyrosine kinases demonstrated that Fyn activity was increased within 10 min of exposure to DMBA, whereas maximal Lck activation required 30 min. Thus, it is likely that the Fyn kinase or other protein-tyrosine kinases may be responsible for the early tyrosine phosphorylation of phospholipase C-gamma 1, which results in inositol 1,4,5-trisphosphate release and mobilization of intracellular Ca2+.
机译：以前的研究表明，免疫抑制和致癌的多环芳香烃7,12-二甲基苯并（a）蒽（DMBA）损害人和鼠淋巴细胞中Ca（2+）依赖的跨膜信号传导。本研究的目的是分析DMBA抑制免疫的潜在机制，并研究其对人T细胞中Ca2 +稳态和抗原受体信号传导的影响。 DMBA通过释放细胞质Ca2 +，使HPB-ALL细胞中Ca2 +含量迅速而持续地增加。 DMBA还抑制HPB-ALL细胞中Ca2 +的抗CD3 / CD4动员，大约在4小时出现一半最大抑制。因此，最初的Ca2 +动员和抗CD3 / CD4反应抑制的动力学是不同的。单独由DMBA诱导的细胞内Ca2 +的快速升高伴随有磷脂酶C-γ1的肌醇1,4,5-三磷酸和酪氨酸磷酸化的快速但短暂的增加。DMBA在HPB-ALL细胞中诱导的酪氨酸磷酸化的模式与抗CD3 / CD4激活所诱导的显着相似。因此，DMBA诱导的磷酸化可以模拟T细胞中的抗原受体激活，这可能导致抗原反应性改变。 DMBA诱导的磷脂酶C-γ1酪氨酸磷酸化的机制可能是由于蛋白质酪氨酸激酶活性的增加，因为发现DMBA会使T细胞受体的活性增加> 2倍相关的Src家族激酶Fyn和Lck。蛋白酪氨酸激酶激活的动力学表明，暴露于DMBA的10分钟内Fyn活性增加，而最大Lck激活需要30分钟。因此，很可能Fyn激酶或其他蛋白酪氨酸激酶可能导致磷脂酶C-γ1的早期酪氨酸磷酸化，从而导致肌醇1,4,5-三磷酸释放和细胞内Ca2 +的动员。

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