本論文研究膠達那黴素 (geldanamycin, GA) 引發逆境反應上游的訊息傳遞，以及其對熱休克蛋白Hsp90表達的調控機制。膠達那黴素是一種袢霉素 (ansamycin) 衍生的苯二酮 (benzoquinone) 化合物，分離自天然抗真菌活性的產物。透過專一性抑制Hsp90的ATPase活性，GA可造成受Hsp90保護之蛋白質 (client proteins) 的去活化、不穩定進而快速分解，這類蛋白質包括調節細胞生長、分化等為數眾多的訊息傳導蛋白，如蛋白質激□，及固醇類荷爾蒙受體等。
近年來，許多報導指出GA會引發熱休克反應，而且細胞內的鈣離子可能參與此一過程。本論文研究中，藉由分析Hsp70誘發量的變化，我們發現包括熱休克因子HSF1、鈣離子及相關的蛋白質激□等上游的訊息調控因子，皆參與GA及瑞迪士可黴素 (radicicol, RA) 調控人類非小細胞肺癌H460細胞的熱休克反應。進一步發現GA會引發鈣離子瞬間流入細胞質而導致Hsp70的迅速誘發。實驗結果證明細胞內鈣離子濃度的變化，以及與鈣離子相關且H7敏感的蛋白質激□，藉磷酸化活化HSF1，參與兩種藥物誘發Hsp70的過程。
另一方面，GA處理過的細胞除了誘發Hsp70，同時也會引發Hsp90表現量的增加。在哺乳動物細胞質中，Hsp90存在兩種主要的同源異構體 (isoform)，即Hsp90alpha與Hsp90beta，即使在不同物種間Hsp90都具有高度的相似性。為了探討Hsp90alpha與Hsp90beta表達的誘導機制，我們利用及時定量PCR (real-time qPCR) 及同位素代謝標定分析，比較GA處理大鼠腦瘤9L細胞時Hsp90alpha與Hsp90betaβ在mRNA及新生蛋白質量的差異，研究結果發現在GA作用下，Hsp90alpha比Hsp90beta有更好的被誘發性，相反的，Hsp90alpha mRNA量卻低於hsp90beta mRNA，在一般情形下細胞中的hsp90beta mRNA的量是Hsp90alpha mRNA的8.8倍，細胞處理GA後則是3.7倍。進一步，我們試圖了解Hsp90alpha與Hsp90beta表達上的差異是否與轉錄後的調控有關，藉體外轉譯實驗計算兩者的轉譯效率，我們發現Hsp90alpha mRNA有相對更高的轉譯作用，在一般情形下Hsp90alpha mRNA的轉譯效率是Hsp90beta mRNA的8.9倍，細胞處理GA後則是5.8倍。實驗結果證明mRNA層面及轉譯過程的差異造成後來Hsp90alpha與Hsp90beta表達的結果。
綜言之，本研究發現GA的作用能透過活化HSF1來誘發Hsp70，此一訊息傳遞過程與細胞內鈣離子濃度的變化及相關蛋白質激□活性有關；GA對于兩種Hsp90同源異構體的調控主要是在提升轉錄作用，最終決定其表達量在於mRNA量的差異及不同的轉譯效率。

Experiments in this thesis were designed to investigate the upstream signaling of GA-induced stress response and elucidate the inductive mechanisms of Hsp90 upon GA treatment.
Geldanamycin (GA), an ansamycin-derivative benzoquinone compound, was originally isolated as a natural product with anti-fungal activity. GA specifically inhibits the essential ATPase activity of Hsp90 results in inactivation, destabilization, and degradation of Hsp90 client proteins, including a wide variety of signal-transducing proteins that regulate cell growth and differentiation, such as protein kinases and steroid hormone receptors.
Recently, several reports have shown that treatment with GA induces a heat-shock response and intracellular calcium may involve in the process. In this study, we found changes in upstream signaling mediators, including HSF1 and calcium, as well as possible involvement of protein kinase in human non-small cell lung cancer H460 cells treated with Hsp90 binding agents (i.e., GA and radicicol). We further found that GA was able to provoke a rapid calcium influx and thereby resulted in an instant induction of Hsp70. Our results demonstrated that calcium mobilization, a calcium dependent and H7-sensitive protein kinase, along with HSF1 activation by phosphorylation, were all involved in the Hsp70 induction process triggered by the drug.
On the other hand, treatment of cells with GA also induced the expression level of Hsp90 other than Hsp70. In mammals, two major cytoplasmic isoforms of Hsp90, known as Hsp90alpha and Hsp90beta, have been identified and found to be highly conserved among different species. In order to examine the expression of Hsp90 isoforms, the levels of mRNA and nascent protein of Hsp90alpha and Hsp90beta in GA-treated rat brain tumor 9L cells were quantitatively examined using real-time qPCR and metabolic labeling analyses. It is found that Hsp90alpha was more inducible compared to Hsp90beta after GA treatment. Interestingly, the hsp90alpha mRNA was, on the contrary, lower than that of hsp90beta. The relative mRNA level of hsp90beta was respectively about 8.8-fold and 3.7-fold that of hsp90alpha under normal condition and upon GA treatment. Furthermore, we examine whether distinct expression of Hsp90alpha and□Hsp90beta is a result of post-transcriptional regulation. The translational efficiency of Hsp90 isoforms employing in vitro translation was further measured. We found that hsp90alpha mRNA revealed highly effective translation. The translational efficiency of hsp90alpha mRNA was respectively about 8.9-fold and 5.8-fold that of hsp90beta under normal condition and upon GA treatment. Our results indicate that differential expression of Hsp90alpha and Hsp90beta is a consequence involving both the distinct mRNA profiles and the differential translation processes.
In conclusion, treatment with GA was able to activate HSF1 and bring about the induction of Hsp70. Intracellular calcium mobilization and related protein kinase activities are involved in signaling for GA. The primary effect of GA on expression of Hsp90 isoforms is according to promote the transcription of both hsp90 genes. The differential expression of□Hsp90alpha and□Hsp90beta is a consequence of both distinct mRNA profiles and differential translation processes.

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