Lovastatin inhibits T-Cell antigen receptor signaling independent of its effects on ras
Lovastatin inhibits T-Cell antigen receptor signaling independent of its effects on ras
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DOI：
10.1182/blood.v88.12.4611.bloodjournal88124611
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发表时间：
1996-12-15
期刊：
影响因子：
20.3
通讯作者：
Koretzky, G
中科院分区：
文献类型：
--
作者：
Goldman, F;Hohl, RJ;Koretzky, G
洛伐他汀是一种降胆固醇药物，具有抗增殖特性，这可能与其抑制蛋白质异戊二烯化有关。我们研究了洛伐他汀通过T细胞抗原受体（TCR）对信号转导的影响。在人Jurkat T细胞系中，洛伐他汀以时间和浓度依赖性方式抑制近端和远端TCR介导的信号传导事件。TCR刺激后CD69表面表达的上调被洛伐他汀阻断，尽管没有观察到佛波酯诱导的CD69表达的抑制。近端TCR介导的信号传导事件，包括细胞内钙动员，磷酸肌醇的产生，和磷脂酶C γ 1的酪氨酸磷酸化，同样受到洛伐他汀的抑制，尽管整体蛋白酪氨酸激酶活性保持完整。在一个Jurkat变异转染人类1型毒蕈碱受体，洛伐他汀也抑制TCR介导的钙动员和磷酸肌醇的生产，但未能影响毒蕈碱受体诱导的反应。相似剂量的洛伐他汀也破坏ras的翻译后加工，抑制ras依赖性信号，包括TCR刺激后丝裂原相关蛋白激酶的磷酸化和活化。这些发现表明，洛伐他汀的抗增殖特性可能是独立的ras，并可能导致从不同的信号转导途径的解偶联蛋白酪氨酸激酶。(C)1996年，美国血液学会。
Lovastatin, a cholesterol-lowering drug, has antiproliferative properties that may be related to its inhibition of protein isoprenylation. We examined the effects of lovastatin on signal transduction via the T-cell antigen receptor (TCR). Lovastatin inhibited both proximal and distal TCR-mediated signaling events in a time- and concentration-dependent manner in the human Jurkat T-cell line. Upregulation of CD69 surface expression after TCR stimulation was blocked by lovastatin, although no inhibition of phorbol ester-induced CD69 expression was noted. Proximal TCR-mediated signaling events, including intracellular calcium mobilization, inositol phosphate production, and tyrosine phosphorylation of phospholipase C gamma 1, were similarly inhibited by lovastatin, although global protein tyrosine kinase activity remained intact. In a Jurkat variant transfected with the human type-1 muscarinic receptor, lovastatin also inhibited TCR-mediated calcium mobilization and inositol phosphate production but failed to affect muscarinic receptor-induced responses. Lovastatin, at similar doses, also disrupted posttranslational processing of ras and inhibited ras-dependent signals, including phosphorylation and activation of mitogen-associated protein kinase after TCR stimulation. These findings suggest that the antiproliferative properties of lovastatin may be independent of ras and could result from uncoupling protein tyrosine kinases from distinct signal transduction pathways. (C) 1996 by The American Society of Hematology.