Menin represses JunD transcriptional activity in protein kinase Cθ-mediated Nur77 expression
Menin represses JunD transcriptional activity in protein kinase Cθ-mediated Nur77 expression
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DOI：
10.1038/emm.2005.57
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发表时间：
2005-10-31
影响因子：
12.8
通讯作者：
Youn, HD
中科院分区：
文献类型：
--
作者：
Kim, H;Lee, JE;Youn, HD
导致胸腺细胞凋亡的TCR信号传导通过孤儿核受体Nur77家族的表达介导。已经显示Nur77启动子被至少两种信号传导途径激活，一种由钙介导，另一种由蛋白激酶C（PKC）介导。已知MEF2D以钙依赖性方式调节Nur77表达。钙调节MEF2D的机制是通过解离钙敏感的MEF2辅阻遏物（Cabin1/HDACs，HDAC4/5）以及与钙调神经磷酸酶激活的转录因子NF-AT和辅激活因子p300的结合。然而，很少有人知道PKC如何激活Nur77启动子。在此，我们报告PKC θ靶向Nur77启动子中的AP-1样反应元件，其中JunD组成性结合。PKC theta与p300协同作用，触发丝裂原活化蛋白激酶介导的JunD磷酸化，并增加JunD的转录活性。Menin通过募集mSin3-istone脱乙酰酶被鉴定为JunD的转录辅阻遏物。事实上，Menin抑制PKC theta/p300介导的JunD在T细胞中的转录活性。它与JunD一起动态调节组蛋白修饰剂，负责PKC θ对T细胞中Nur77表达的协同作用。
TCR signaling leading to thymocyte apoptosis is mediated through the expression of the Nur77 family of orphan nuclear receptors. It has been shown that the Nur77 promoter is activated by at least two signaling pathways, one mediated by calcium and the other by protein kinase C (PKC). MEF2D has been known to regulate Nur77 expression in a calcium-dependent manner. The mechanism by which calcium regulates MEF2D is through dissociation of calcium-sensitive MEF2 corepressors (Cabin1/ HDACs, HDAC4/5) and the association with calcineurin-activated transcription factor NF-AT and the coactivator p300. However, little is known about how PKC activates the Nur77 promoter. Herein, we report that PKC theta targets AP-1 like response element in the Nur77 promoter where JunD constitutively binds. PKC theta triggers mitogen-activated protein kinase-inediated phosphorylation of JunD, and increases transcriptional activity of JunD, cooperatively with p300. Menin is identified as the transcriptional corepressor for JunD via recruitment of mSin3-istone deacetylases. In fact, Menin represses PKC theta/p300-mediated transcriptional activity of JunD in T cell. Its dynamic regulation of histone modifiers with JunD is responsible for PKC theta-synergistic effect on Nur77 expression in T cell.