主題演講：A Tale of Two Translocations: Lessons for Leukaemia
兩個基因位移的故事：白血症的經驗
The past 30 years have seen amazing advances in understanding the molecular lesions underlying cancer development. Many leukemias and lymphomas harbour specific chromosome abnormalities and these have proved to be a rosetta stone for identifying the causative oncogenic mutations. Those in human Burkitt’s lymphoma and follicular lymphoma activate very different genes: myc and bcl-2 respectively. Studies using transgenic mice demonstrated causality and illuminated the contribution of each gene to the tumorigenic process. The lessons learned are applicable to many types of cancer.
過去三十年中在瞭解癌症發展的過程中所牽涉到的分子生物受損機制，已有了長足的進展。許多白血症和淋巴腫瘤的病例，被證明帶有特定的染色體變異，也因此這些資訊被認為是可用來解讀造成癌症基因的<
<羅賽達石>
>。人類的柏基氏淋巴腫瘤和濾胞淋巴腫瘤，會分別啟動兩組不同的 myc及 bcl-2基因。以基因轉殖鼠對這兩組基因的研究，發現到每組基因對腫瘤形行成所拌演的角色。從這研究過程所獲得的資訊，可以引用到其他種類癌症的研究。
(註 ：羅賽達石1799發掘自埃及羅賽達村的碑石。並載有古希臘文及古埃及文，成為日後解讀古埃及文的指標。)
大師演講：The Bcl-2 Life/Death Switch in Cancer Development and Therapy
Bcl-2 活存/死亡基因在癌症發展及治療的角色
Impairment of the physiologic cell death process (apoptosis) is a critical step in the development of cancer and a major impediment to effective therapy.? Bcl-2, the oncoprotein activated by chromosome translocation in human follicular lymphoma, inhibits cells from undergoing apoptosis in response to many cytotoxic agents. A score or so Bcl-2 relatives have been identified in mammalian cells.? The closest homologs (Bcl-xL, Bcl-w, Mcl-1 and A1) are also anti-apoptotic but others are instead pro-apoptotic. While the pro-apoptotic proteins Bax and Bak are very similar to Bcl-2 in sequence and structure, the ‘BH3-only proteins’ are largely unrelated, apart from the signature BH3 (Bcl-2 homology region 3) domain that is essential for their killing function. Collectively, the Bcl-2 family functions as a ‘life/death switch’ that arbitrates whether or not a cell should activate the caspase-driven proteolytic cascade responsible for cellular demolition. Our recent in vivo studies suggest that small molecules mimicking BH3 domains will be effective cancer therapeutics.
細胞凋零過程中所牽涉到的瑕疵，是造程癌症發生的關鍵步驟，也妨礙了對癌症的有效的治療。Bcl-2(人類濾胞腫瘤所引起的因為基因位移，而產生的致癌蛋白）會抑制許多細胞在面臨有毒物質時應進行的細胞凋零反應。約有二十多種這一家族的蛋白，已在哺乳類細胞被鑑定出來。與 Bcl-2最相近的 Bcl-xL, Bcl-w, Mcl-1和A1已知會抑制細胞凋零，但其它的則是會促進細胞凋零。雖然能促進細胞凋零的Bax 及Bak蛋白在序列及結構上與 Bcl-2很相似，但是 BH3-專一蛋白卻與它無關，而在致死功能上則扮演重要的角色。整體而言，Bcl-2家族的功能類似一組生存或死亡的開關，能決定是否啟動由半胱天冬?主導的蛋白分解作用的進行。我們最近的活體實驗結果顯示，在小分子上模擬 BH3結構，在癌症治療上非常有效。 |
