臺灣博碩士論文加值系統

酪胺酸酶 (tyrosinase)為黑色素生合成過程中速率決定酵素，酪胺酸酶的表現需要經由一連串的訊息傳遞調控，黑色素生合成之訊息傳遞並未完全確認，然而，許多研究已證實，cAMP 在黑色素生合成調控上扮演重要角色，cAMP經由活化microphthalmia-associated transcription factor (MITF)使酪胺酸酶表現；cAMP也可經由一連串訊息傳遞分子活化extracellular signal regulated kinase(ERK)，而使MITF 水解，降低酪胺酸酶表現；除此之外，cAMP 可經由抑制phosphatidylinositol 3-kinase (PI3K)之活化，抑制protein kinase B (Akt)表現，促進MITF的表現，增加酪胺酸酶的表現，經由上述訊息傳遞可調控黑色素生合成。
黑色素生合成須經由一連串氧化還原反應步驟形成，而許多美白有效成分具有抗氧化能力，如維生素C，為還原劑，可將黑色素生合成步驟中的中間產物還原，減緩黑色素生合成。藻青素 (c-phycocyanin)為藍綠藻主要成分之ㄧ，研究指出藻青素具有抗氧化的特性，因此，我們研究藻青素是否影響黑色素生合成並觀察其是否影響黑色素生成訊息傳遞的分子。由實驗結果得知，藻青素使酪胺酸酶活性下降並使其mRNA 以及蛋白質表現量減少；藻青素可降低MITF 之mRNA 與蛋白質表現，並且可活化ERK。我們進一步利用PD98059抑制ERK 的活化，發現當ERK 活化受到抑制後，藻青素抑制酪胺酸酶的效果
即降低。因此，藻青素可經由抑制MITF 表現以及活化ERK 使MITF 水解的途徑抑制酪胺酸酶表現，進而達到抑制黑色素生合成的效果。

Tyrosinase catalyzes the rate-limiting reaction of melanogenesis. The formation of melanin is regulated by the activity or the expression of the enzyme. Although the whole picture of the signal transduction involved in melanogenesis remains unclear, it is
suggested that cAMP plays an important role in the biosynthesis. cAMP modulates melanogenesis in three aspects. Firstly, cAMP activates the expression of microphthalmia associated transcription factor (MITF), which is the transcription factor of tyrosinase.
Secondly, cAMP induces MITF degradation through the activation of ERK, and therefore, down-regulates the expression of tyrosinase. Thirdly, cAMP inhibits the activation of phosphatidylinositol 3-kinase (PI3K), which results in the repression of protein kinase B
(Akt) expression, yet up-regulates MITF.
Melanogenesis is involved in a series of redox reactions. Some antioxidants such as ascorbic acid, retard melanogenesis through reverse the process by reduction of oxidized intermediates. C-phycocyanin (CPC), a component of blue green algae, has been studied to have anti-oxidative capacity. In this study, we investigate the inhibitory effect of CPC on melanogenesis. Results showed that CPC attenuated melanogenesis via reduced tyrosinase activity and expression. The reduced level of tyorsinase expression was due to the
activation of ERK, which phosphorylated MITF and consequently leaded to MITF degradation. Besides, the decreased level of MITF was also observed at transcriptionallevel. In conclusion, CPC reduced melanin biosynthesis by activation of ERK and decreased level of MITF transcription; therefore, resulted in subsequent down-regulation of tyrosinase.

目錄
中文摘要.............................................................I
英文摘要............................................................II
目錄................................................................IV
圖目錄.............................................................VII
第一章 緒論...........................................................1
一、引言.............................................................1
二、皮膚的構造與生理..................................................2
1. 皮膚的外觀與功能...................................................2
2. 表皮.............................................................2
3. 真皮.............................................................5
4. 皮下脂肪組織.......................................................5
三、黑色素...........................................................5
1. 黑色素生合成......................................................5
2. 抑制黑色素形成之方法................................................8
3. 抗氧化劑與黑色素生合成..............................................9
4. 細胞中黑色素生合成之訊息傳遞.........................................9
四、藻青............................................................13
五、研就動機與目的....................................................15
第二章 實驗材料......................................................16
一、 細胞株來源......................................................16
二、 實驗藥品........................................................16
三、 抗體...........................................................19
四、 實驗器材........................................................20
五、 實驗試劑配製....................................................22
第三章 實驗方法......................................................27
一、 黑色素細胞瘤細胞細胞株培養........................................27
二、 細胞存活率測定..................................................27
三、 酪胺酸酶酵素活性測試.............................................28
四、 黑色素含量分析..................................................30
五、 西方墨點法 (Western blotting) ..................................30
六、 反轉錄聚合酶連鎖反應(Reverse transcription polymerase chain reaction,RT-PCR)...................................................34
七、 同步定量反轉錄聚合酶連鎖反應 (Real-Time PCR; Q-PCR) ...............35
第四章 實驗結果......................................................37
一、 不同劑量c-phycocyanin 作用於黑色素瘤細胞之細胞型態與細胞存活的情形.37
二、 C-phycocyanin 對於細胞中酪胺酸酶活性與黑色素含量之影響.............37
三、 分析細胞中抑制黑色素生成之訊息傳遞途徑.............................38
1. C-phycocyanin 對於細胞中酪胺酸酶之影響.............................38
2. C-phycocyanin 對於酪胺酸酶之transcription factor：MITF 之影響.....39
3. C-phycocyanin 對於ERK 1/2 與RSK 1 之影響.........................40
4. C-phycocyanin 對於Akt 之影響.....................................41
5. 加入MEK inhibitor (PD98059)以及c-phycocyanin 對於酪胺酸酶之影響..41
第五章 討論........................................................42
一、 C-phycocyanin 對於黑色素生合成之抑制.............................42
二、 C-phycocyanin 抑制黑色素生合成之訊息傳遞路徑......................43
1. c-phycocyanin 對於MITF 之影響....................................43
2. c-phycocyanin 對於ERK 1/2 與RSK 1 之影響.........................44
3. c-phycocyanin 對於Akt 之影響.....................................44
4. 加入MEK inhibitor (PD98059)以及c-phycocyanin 對於酪胺酸酶之影響....45
5. 其他訊息傳遞分子..................................................46
第六章 結論.........................................................47
第七章 未來展望......................................................47
參考文獻............................................................48

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