Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells
Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells
复制标题
DOI：
10.1038/onc.2009.142
复制
发表时间：
2009-08-01
期刊：
影响因子：
8
通讯作者：
Horn, F.
中科院分区：
文献类型：
--
作者：
Bauer, K.;Kretzschmar, A. K.;Horn, F.
信号转导子和转录激活子3（Stat3）是白细胞介素6（IL-6）家族细胞因子的主要介导因子。此外，已知Stat3参与许多恶性肿瘤的病理生理学。在这里，我们表明，顺式-反式肽基脯氨酰异构酶亲环素（Cyp）B特异性地与Stat3相互作用，而高度相关的CypA不。CypB敲低抑制IL-6诱导的反式激活潜力，但不抑制Stat 3的酪氨酸磷酸化。CypB与Stat3靶启动子的结合以及Stat3在CypB耗竭时核内定位的改变表明Stat3/CypB相互作用的核功能。相反，CypA敲低抑制Stat3 IL-6诱导的酪氨酸磷酸化和核转位。Cyp抑制剂环孢菌素A（CsA）引起类似的效果。然而，Stat1激活响应IL-6或干扰素-γ不受Cyp沉默或CsA治疗。因此，Cyp敲低将IL-6信号传导转移到Stat1主导的途径。此外，Cyp耗竭或CsA治疗诱导IL-6依赖性多发性骨髓瘤细胞凋亡，而IL-6非依赖性细胞系不受影响。因此，Cyps支持Stat3的抗凋亡作用。总的来说，CypA和CypB都在不同的信号水平上对Stat3的激活和功能起着关键作用。这些数据还表明了CsA作用的一种新机制。Oncogene（2009）28，2784 - 2795; doi：10.1038/onc.2009.142; 2009年6月8日在线发表
Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/ CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon-gamma was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action. Oncogene ( 2009) 28, 2784-2795; doi:10.1038/onc.2009.142; published online 8 June 2009