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Cellular and Molecular Biology Lab

師:人大部分的反應都源自於基因的功能!

生:咦,那基因的功能為何呢?

師:基因幾乎決定一切細胞的生理作用!

生:那人是不是有很多個基因呢?

師:看你問的是哪一類型基因,若是能製造出蛋白質的基因,人類不到兩萬個!

生:這麼少嗎?難怪我覺得自己頭腦很簡單…….

師:@#$%︿&

生:那我們怎麼知道基因的功能呢?

師:來來來,進來實驗室,讓我慢慢跟你說~~

生嘀咕:吼~早知道就不要問這麼多$%^&*

師:skin young again!!?(皮又在養嗎?)

人類大部分的基因功能尚未解開,為了瞭解新基因的功能,我們以基因晶片與生物資訊法挑選人類腫瘤細胞中表現異常的新型基因(功能尚未被解開的基因),或以免疫共沉澱尋找已知具致癌特性的蛋白質激酶或甲基轉移酶的受質,再以細胞培養為模式系統,研究該新型基因或蛋白質修飾的功能。我們將基因或蛋白質修飾突變體表達在模式細胞中,再觀察細胞的行為變化,包括細胞轉型、細胞分裂的速度、細胞轉移、細胞週期的行進、染色體的分佈、紡槌絲的型態、和動物腫瘤生成等,以此推斷該基因之是否具致細胞轉形功能。依此原則,我們找到了多個潛在致癌或抑癌蛋白,可以造成動物腫瘤生成或抑制腫瘤細胞增生。接下來分析該基因如何達成其細胞功能部分,我們先觀察其蛋白質特性包括細胞內分佈與可能之蛋白質修飾,再透過尋找該(修飾)蛋白質的細胞內交互作用蛋白,來瞭解該蛋白是透過何種機制來執行其細胞功能。基於此流程,我們發現Aurora-A透過磷酸化HURP來活化NF-kB,以加快細胞週期G1/S的行進並促進細胞轉型;Aurora-A磷酸化Astrin並調節後者的蛋白質交互作用活性,繼而解除Astrin對細胞週期分裂期行進之限制;PRMT5與MEP50甲基化PI3K來促進細胞存活與轉型;我們所命名的新穎型蛋白SLAN抑制致癌蛋白Aurora-A活性並控制細胞分裂中軸線的功能,藉以抑制細胞轉型等。此外,我們也發現去磷酸化酶PP1 alpha與醣解作用酵素ENO1差別性地增強肺癌細胞的轉型活性,對食道癌等其他細胞卻無此作用。我們接下來分析臨床檢體,檢視先前發現的基因或是致癌分子途徑是否在腫瘤檢體中表現異常,藉以衡量細胞或動物模式中的致癌理論是否正確。我們期待這樣的檢視流程可以找到更精準的腫瘤標記,或是影響腫瘤生成的分子途徑,以提供未來克制癌症的新利器!經過以上挑選之後找到的基因,深入探討其在 細胞內的功能,發現很多基因參與在胞器或是其他細胞結構例如細胞骨架的調控。例如被Aurora-A磷酸化所產生的HURP p725,能夠匯同細胞骨架Vimentin形成新月形骨架模板,接著透過吸引並穩定多種高基氏體,來促進高基氏體形成Golgi ribbon,而此型態的高基氏體方具有刺激細胞移行的活性;再者,PRMT5甲基化HURP於R122後,能夠連結並穩定乙醯化微管,繼而僵固化高基氏體而使其失去刺激細胞移行的能力。而以上修飾的HURP或Vimentin皆能促進聚集體胞器的產生,此能促進癌細胞清除錯疊蛋白並利其存活。以上發現皆表示,癌症的發生應與此等細胞內結構或胞器的失衡有關係,因此,目前實驗室的方向便鎖定在胞器或是細胞骨架與細胞癌化的關係 (請見下圖與研究介紹)。

We have been focusing our efftorts on decoding the mechanisms by which cancers develop. The lab reaches its current status through three stages. Stage 1, we searched for the genes with altered expression in collected cancer tissues, and from which, several cancer promoting or inhibiting genes have been identified.   Alternatively, we identified substrates of known oncogenic kinase or methyltransferase, and analyzed the potential cell transforming activities of such modifications. Stage 2, we explored how those cancer related genes or protein modifications contribute to cancer formation by integrating them into well-established oncogenic circuits, including cell cycle  progression pathways, cell survival networks and cell migration cascades. Stage 3, we found that many of the cancer related proteins or modified substrates localized to organelles or associated with cytoskeletons such as Golgi apparatus, centrosome, aggresome, and microtubule or Vimentin. We are on the process unraveling the potential contribution of those organelles or organelle-associated cytoskeletons to cancer development. Our current study shows that Golgi apparatus may be linked to cell cycle progression and cell migration,  centrosome contributes to aggresome formation which is employed by cancer cells to survive during misfolded proteins are extensively accumulated, and microtubule and Vimentin are crucial for Golgi or aggresome formation and subsequent cell migration. In conclusion, it is pointed out that many cancer related genes or protein modifications enhance cancer formation through abnormally manipulating the status of certain organelles, thereby creating a new direction toward the understanding of how cancers grow.

stage 1

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stage 2

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stage 3

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