T 淋巴細胞的增生，成熟，活化與死亡為一個動態的過程且終將趨於恆定以維持平衡。若活化增生等過程失去調控，則可能造成異常大量增生並促成自體免疫的發生。細胞凋亡為一重要的調控機制，能剔除過度活化或發育不良的細胞，以維持細胞發育恆定。Phorbol myristate acetate (PMA) 為diacylglycerol的相似物，可和Protein kinase C結合並活化下游Ras/Raf/MEK/ERK等訊息傳遞。此訊號傳遞與T細胞受體所引發的活化機制非常相似。PMA依據作用濃度及細胞特性，能促使包含T 細胞等多種不同類型細胞的進行分化，或能引起細胞死亡。PMA也能保護T細胞株免於Fas引起的細胞凋亡。另也有研究指出PMA能刺激攝護腺癌細胞株釋出腫瘤壞死因子TNF-alpha而引起細胞凋亡。然而，PMA如何能引發T細胞凋亡，及其詳細機制仍不明。
在此篇論文中，我針對能引發細胞凋亡的腫瘤抑制蛋白WWOX/WOX1進行研究，並探討其是否參與在PMA引發的T細胞凋亡現象中。雙色胺酸功能區氧化還原酶WW domain-containing oxidoreductase，WWOX，又稱作WOX1、FOR，已知當在乳癌或攝護腺癌等多種細胞株中過度表現此蛋白，可引起細胞凋亡。且在性荷爾蒙、紫外線以及其他促使細胞凋亡的刺激下，WOX1的第一個WW domain中的第33號胺基酸Tyrosine會被磷酸化，進而活化WOX1。此活化的WOX1可和磷酸化的p53結合，接著一同移動到粒線體或細胞核內引發細胞凋亡。在初步研究中發現高濃度 (micromolar) 的PMA刺激Jurkat T細胞株，在30分鐘內能引起ERK磷酸化以及WOX1蛋白表現量上升，在24小時內引發DNA斷裂以及死亡。而當以MEK抑制物U0126預先處理Jurkat T細胞時，可抑制細胞死亡，顯示PMA引發的Jurkat T 細胞死亡和MEK訊號途徑有關。相反的，當預先處理U0126於未完全分化成熟的Molt-4 T細胞株，則促進了PMA引發的細胞死亡現象。
從免疫沈澱的實驗結果顯示，WOX1和MEK1相互結合在一起。當給予高濃度的PMA刺激下，在極短時間內WOX1和MEK1就相互解離。解離後的WOX1可能被活化，進而增加細胞死亡或抑制細胞生長的可能性。預先處理U0126則可抑制PMA引起的WOX1解離現象。利用dominant-negative WOX1能抑制wild type WOX1的特性，在Jurkat T細胞表現dominant negative WOX1可抑制PMA引起的DNA斷裂現象。綜合研究結果，證明了WOX1的確參與在 PMA引發的Jurkat T細胞凋亡之中，並扮演決定性的重要角色。由MEK1和WOX1的結合作用，推測其限制了WOX1被活化、入核的路徑，進一步阻斷WOX1所調控的細胞凋亡而使細胞利於存活。

T lymphocyte homeostasis involves proliferation, maturation, activation and death. Dysregulation of T cell activation may lead to abnormal proliferation, contributing in part to autoimmune disease. Apoptosis is a quality control process to eliminate unwanted T cells. Phorbol myristate acetate (PMA) mimicks the function of diacylglycerol (DAG) in binding to PKC and activating downstream Ras/Raf/MEK/ERK pathway. This signaling acts similarly to ligand-induced T cell receptor (TCR) activation pathway. PMA plays dual roles in T cell differentiation and apoptosis. At nanomolar levels, PMA induces differentiation in various types of cells, and also protects T cells from Fas-mediated programmed cell death. Notably, PMA promotes apoptosis of prostate cancer cells via autocine TNF-alpha. However, the mechanisms underlying PMA-mediated T cell death are largely unknown.
Here, I show the participation of tumor suppressor WOX1 in the death event. WW domain-containing oxidoreductase, literally WWOX, FOR or WOX1, induces apoptosis in many cell types when overexpressed. WOX1 is phosphorylated at Tyr33 in the first WW domain upon stimulation with hormones or apoptotic stress stimuli. Activated WOX1 and p53 physically interact, and relocate into mitochondria and nucleus to induce apoptosis synergistically. Micromolar levels of PMA rapidly induced ERK phosphorylation and WOX1 expression in less than 30 min, and subsequent death in 24 hr in Jurkat T cells (determined by DNA fragmentation and cell cycle analysis). When these cells were pretreated with MEK inhibitor U0126, PMA-induced cell death was blocked. In contrast, PMA and U0126 synergistically enhanced cell death in less differentiated Molt-4 T cells.
By co-immunoprecipitation, WOX1 was shown to physically interact with MEK1, followed by rapid dissociation upon PMA stimulation. Dissociation of WOX1 may increase the chances of cell death or growth suppression. U0126 blocked PMA-induced dissociation of MEK1/WOX1 complexes. Functional suppression by dominant-negative WOX1 inhibited PMA-induced DNA fragmentation in Jurkat T cells. Taken together, WOX1 participates in T cell death caused by PMA. Binding of WOX1 by MEK1 appears to block relocation of WOX1 to the nuclei, thus providing a regulatory control for T cell survival.

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