周獻堂2006-07-262018-07-112006-07-262018-07-112000http://ntur.lib.ntu.edu.tw//handle/246246/22848JAK/STAT 在血液細胞的訊息傳遞路徑中扮演著非 常重要的角色。藉由JAK/STAT 使cytokine 的訊 息能藉由刺激細胞膜上的receptor 一步步地傳達 到細胞核內以啟動基因的表達。此路徑傳遞血液 細胞絕大部分的生長和分化訊息。目前文獻顯示 所有須與cytokine receptor superfamily 結合 的cytokine 都能活化JAK tyrosine kinase family。 因為JAK/STAT 路徑在血液細胞訊息傳遞路徑中扮 演著非常重要的角色，所以推論JAK/STAT 路徑亦 應在血癌的生成機轉中佔重要的角色。愈來愈多 的證據支持此學說，最近TEL-JAK2 致癌基因在三 個血癌病人細胞中被發現。此致癌基因能使細胞 變性轉型的能力是來自於藉由TEL 的PNT domain 使JAK2 的kinase domains 彼此結合 (oligomerization)而持續保有JAK2 kinase 的活 性。 TEL-JAK2 的致癌生成機轉, 主要來自於其kinase domain 上的酪氨酸基被持續磷酸化。尋找TELJAK2 的下游受脢質蛋白, 對了解癌症的生成機轉 之謎, 是很重要的. 我們已clone hTEL-mJAK2 , 且證明TEL-JAK2 的持續保有酪氨酸激脢的特性, 能使 Ba/F3 細胞株由cytokine-dependent 轉型 成cytokine-independent. 而且我們利用TELJAK2 的持續保有酪氨酸激脢的特性, 發現一個持 續被酪氨酸磷酸化的受脢質蛋白, 只存在於已轉 型的Ba/F3/ TEL-JAK2 細胞, 但不出現在未轉型 的Ba/F3/ TEL-JAK2 細胞. 目前正進而研究它的 生物特性, 以了解血癌的生成機轉.The JAK/STAT (Janus protein tyrosine kinase/Signal Transducers and Activators of Transcription) pathway has emerged as a major signal transduction mechanism in hematopoietic system, linking cell surface receptors on the membrane to transcriptional events in the nucleus. This pathway plays critical roles in transducing growth and differentiation signals emanating from ligand-activated cytokine receptor complexes. It was demonstrated that all the cytokines that utilize receptors of the cytokine receptor superfamily were capable of activating members of the JAK tyrosine kinase family. The importance of the JAK/STAT pathway in cytokine signaling for the hematopoietic cells suggests a potential role in the pathogenesis of hematological malignancies. Some evidences have supported this hypothesis. The TEL-Jak2 fusion oncogene has recently been found in 3 leukemia patients. The oligomerization by the PNT domain of TEL leads to constitutive activation ( phosphorylation) of the Jak2 tyrosine kinase domain, which is necessary for cellular transformation. The constitutive tyrosine phosphorylation of the tyrosine kinase domain of TEL-Jak2 plays the critical role for the leukemogenesis. To try to find the downstream substrate of the TEL-Jak2 is very important for the understanding the signal transduction pathway for the leukemogenesis. We have constructed the hTELmJAK2 oncogene including the human TEL-specific oligomerization domain and the catalytic domain of murine JAK2. And our data also showed the TELinduced oligomerization of TEL-JAK2 resulted in the constitutive activation of its tyrosine kinase activity and conferred cytokine (IL-3)-independent proliferation to the IL-3-dependent Ba/F3 hematopoietic cell line. We have also identified one strongly constitutively tyrosine-phosphorylated protein in the Ba/F3/TEL-JAK2 cells which is not found in the Ba/F3 parent cells by using the character of the constitutively activated catalytic activity of TEL-JAK2. We are studying the biological character of this down-stream substrate of TEL-JAK2 oncogene to elucidate the signal transduction pathway for leukemogenesis in the hematopoietic system.application/pdf54340 bytesapplication/pdfzh-TW國立臺灣大學醫學院小兒科reporthttp://ntur.lib.ntu.edu.tw/bitstream/246246/22848/1/892314B002055.pdf