Kim Hyungsoo, Lee Ji Eun, Kim Bu Yeon, Cho Eun Jung, Kim Seong Tae, Youn Hong Duk
Department of Biochemistry and Molecular Biology, Cancer Research Institute, Seoul National University, College of Medicine, 28 Yongon-dong, Chongro-gu, Seoul 110-799, Korea.
Exp Mol Med. 2005 Oct 31;37(5):466-75. doi: 10.1038/emm.2005.57.
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 PKCtheta targets AP-1 like response element in the Nur77 promoter where JunD constitutively binds. PKCtheta 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 PKCtheta/p300-mediated transcriptional activity of JunD in T cell. Its dynamic regulation of histone modifiers with JunD is responsible for PKCq-synergistic effect on Nur77 expression in T cell.
导致胸腺细胞凋亡的TCR信号传导是通过孤儿核受体Nur77家族的表达介导的。研究表明，Nur77启动子至少由两条信号通路激活，一条由钙介导，另一条由蛋白激酶C（PKC）介导。已知MEF2D以钙依赖的方式调节Nur77的表达。钙调节MEF2D的机制是通过钙敏感的MEF2共抑制因子（Cabin1/HDACs、HDAC4/5）的解离以及与钙调神经磷酸酶激活的转录因子NF-AT和共激活因子p300的结合。然而，关于PKC如何激活Nur77启动子知之甚少。在此，我们报道PKCtheta靶向Nur77启动子中JunD组成性结合的AP-1样反应元件。PKCtheta触发丝裂原活化蛋白激酶介导的JunD磷酸化，并与p300协同增加JunD的转录活性。通过募集mSin3-组蛋白去乙酰化酶，Menin被确定为JunD的转录共抑制因子。事实上，Menin在T细胞中抑制PKCtheta/p300介导的JunD转录活性。它与JunD对组蛋白修饰剂的动态调节负责PKCq对T细胞中Nur77表达的协同作用。
