Rapamycin inhibits proteasome activator expression and proteasome activity
Rapamycin inhibits proteasome activator expression and proteasome activity
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雷帕霉素抑制蛋白酶体激活剂表达和蛋白酶体活性
DOI：
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发表时间：
1997
影响因子：
5.4
通讯作者：
Jiangping Wu
中科院分区：
文献类型：
--
作者：
Xin Wang;S. Ōmura;Luc I. Szweda;Y. Yang;J. Bérard;Johnny Seminaro;Jiangping Wu
雷帕霉素（RAPA）是一种有效的免疫抑制药物，其某些直接或间接靶点可能对免疫反应的调节至关重要。在这项研究中，我们使用差异杂交来寻找人类基因的表达是敏感的RAPA。发现了7个RAPA敏感基因，其中一个编码与蛋白酶体激活剂α亚基（PA 28 α）高度同源的蛋白质。后来发现该基因编码蛋白酶体激活剂的β亚基（PA 28 β）。活化的T和B细胞在mRNA水平上调了PA 28 β表达。RAPA、FK506和环孢菌素A可抑制这种上调。RAPA和FK506还抑制了植物血凝素（PHA）刺激的T细胞中上调的PA 28 α信息。免疫印迹和共聚焦显微镜观察表明，RAPA在蛋白水平上抑制活化T细胞中的PA28α和PA28β。可能作为一个结果，有一个四倍的PHA激活后，外周血单核细胞裂解物中的蛋白酶体活性增加。RAPA可抑制蛋白酶体活性增强部分。考虑到蛋白酶体在降解调节蛋白中所起的关键作用，我们的数据表明蛋白酶体激活剂是雷帕霉素的相关和重要的下游靶点，并且免疫应答可以通过蛋白酶体的活性来调节。
Rapamycin (RAPA) is a potent immunosuppressive drug, and certain of its direct or indirect targets might be of vital importance to the regulation of an immune response. In this study, we used differential hybridization to search for human genes whose expression was sensitive to RAPA. Seven RAPA‐sensitive genes were found and one of them encoded a protein with high homology to the α subunit of a proteasome activator (PA28α). This gene was later found to code for the β subunit of the proteasome activator (PA28β). Activated T and B cells had up‐regulated PA28β expression at the mRNA level. Such up‐regulation could be suppressed by RAPA, FK506, and cyclosporin A. RAPA and FK506 also repressed the up‐regulated PA28α messages in phytohemagglutinin (PHA)‐stimulated T cells. At the protein level, RAPA inhibited PA28α and PA28β in the activated T cells according to immunoblotting and confocal microscopy. Probably as a consequence, there was a fourfold increase of proteasome activities in the peripheral blood mononuclear cell lysate after the PHA activation. RAPA could inhibit the enhanced part of the proteasome activity. Considering the critical role played by the proteasome in degrading regulatory proteins, our data suggest that the proteasome activator is a relevant and important downstream target of rapamycin, and that the immune response could be modulated through the activity of the proteasome.
DOI：
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发表时间：
1994-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
C. Realini;W. Dubiel;G. Pratt;K. Ferrell;M. Rechsteiner
通讯作者：
C. Realini;W. Dubiel;G. Pratt;K. Ferrell;M. Rechsteiner
DOI：
10.1073/pnas.91.8.3191
发表时间：
1994-04-12
影响因子：
11.1
作者：
LYONS, WE;GEORGE, EB;SNYDER, SH
通讯作者：
SNYDER, SH