Wedelolactone, a Naturally Occurring Coumestan, Enhances Interferon-γ Signaling through Inhibiting STAT1 Protein Dephosphorylation
Wedelolactone, a Naturally Occurring Coumestan, Enhances Interferon-γ Signaling through Inhibiting STAT1 Protein Dephosphorylation
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DOI：
10.1074/jbc.m112.442970
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发表时间：
2013-05-17
影响因子：
4.8
通讯作者：
Yu, Qiang
中科院分区：
文献类型：
--
作者：
Chen, Zhimin;Sun, Xiaoxiao;Yu, Qiang
信号转导子和转录激活子1（STAT 1）转导来自细胞因子和生长因子（特别是IFN-γ）的信号，并调节参与细胞存活/死亡、增殖和迁移的基因的表达。STAT 1通过JAK在其酪氨酸701上的磷酸化而被激活，并且通过酪氨酸磷酸酶的去磷酸化而失活。我们发现了一种天然化合物，wedelolactone，通过抑制STAT 1去磷酸化和通过特异性抑制T细胞蛋白酪氨酸磷酸酶（TCPTP）（一种重要的STAT 1去磷酸化酪氨酸磷酸酶）延长STAT 1激活来增加IFN-γ信号传导。更有趣的是，wedelolactone通过与TCPTP的C-末端自抑制结构域相互作用来抑制TCPTP。我们还发现，wedelolactone协同IFN-γ诱导肿瘤细胞凋亡。我们的数据表明抗癌或抗增殖药物的新靶点，特异性调节PTPs的新机制，以及治疗癌症或其他增殖性疾病的新候选药物。
Signal transducers and activators of transcription 1 (STAT1) transduces signals from cytokines and growth factors, particularly IFN-gamma, and regulates expression of genes involved in cell survival/death, proliferation, and migration. STAT1 is activated through phosphorylation on its tyrosine 701 by JAKs and is inactivated through dephosphorylation by tyrosine phosphatases. We discovered a natural compound, wedelolactone, that increased IFN-gamma signaling by inhibiting STAT1 dephosphorylation and prolonging STAT1 activation through specific inhibition of T-cell protein tyrosine phosphatase (TCPTP), an important tyrosine phosphatase for STAT1 dephosphorylation. More interestingly, wedelolactone inhibited TCPTP through interaction with the C-terminal autoinhibition domain of TCPTP. We also found that wedelolactone synergized with IFN-gamma to induce apoptosis of tumor cells. Our data suggest a new target for anticancer or antiproliferation drugs, a new mechanism to regulate PTPs specifically, and a new drug candidate for treating cancer or other proliferation disorders.