中文摘要
鉛化物為普遍之環境污染物，會誘發細胞轉型以及老鼠腫瘤形成。流行病學研究評估指出，鉛可能與人類肺癌、胃癌、膀胱癌形成有關。鉛誘發哺乳類細胞基因突變的能力不強，然而它能活化一些生物訊號傳遞路徑。為了瞭解鉛誘發之訊號分子影響基因毒性的機制，本篇論文探討哺乳類細胞在醋酸鉛的處理下，生長素活化激酶(MAPKs)及AKT訊號傳遞路徑調控核酸修補及細胞與基因毒性的情形。鉛處理人類肺癌細胞株CL3會造成磷酸化ERK1/2及AKT含量的增加，但並不活化ERK5、p38以及JNK。鉛活化ERK1/2的持久性比其誘發AKT活化更長，並且這兩種訊號傳遞路徑並無交互關係。以PD98059抑制ERK1/2之上游活化激酶MKK1/2，顯著地促使鉛對CL3細胞以及人類纖維母細胞誘發hprt基因突變率及加強細胞毒性。相反地，以wortmannin抑制CL3細胞中AKT之上游活化激酶PI3K並不影響鉛之細胞與基因毒性。氫氧自由基清除劑甘露醇會抑制鉛活化ERK1/2的能力，且甘露醇可降低PD98059與鉛共同處理CL3細胞造成的細胞毒性與基因突變率。鉛的細胞毒性與基因突變率和細胞內缺鹼基位內切酵素(APE)的含量成反比。鉛可加強CL3細胞之APE內切酵素活性，且共同處理PD98059會降低鉛誘發缺鹼基位的修補速率，暗示鉛活化ERK1/2可加強鹼基切除修補(base excision repair; BER)能力。另外，鉛對缺乏核酸切除修補(nucleotide excision repair; NER)能力的細胞誘發之基因毒性與細胞毒性顯著地高於對照組細胞。鉛會增加CL3細胞NER之核酸修補合成能力，且PD98059會顯著降低此活性，相反地，將持續活化態的MKK1轉殖表現於CL3細胞會增加此核酸修補合成能力。利用基因微陣列技術，我們發現鉛透過ERK1/2訊號路徑促使一些核酸修補酵素、抗氧化酵素及癌轉移等基因的表達。綜合上述，鉛會對細胞產生氫氧自由基而傷害基因，鉛也能藉由氫氧自由基活化ERK1/2訊號傳遞路徑以增加BER及NER來保護鉛的基因毒害，但是鉛活化ERK1/2也可能會誘發癌轉移。

本篇論文進而探討鉛持久性活化ERK1/2訊號傳遞路徑的機制。鉛持久性活化ERK1/2並不全然決定於上游Ras-Raf-MKK1/2之訊號。有趣地，隨著鉛處理的時間與劑量的增加，MKP-1去磷酸酶的蛋白質含量隨之下降，且此趨勢與鉛長效地活化ERK1/2呈正相關。鉛能促使MKP-1被ubiquitination，然而，鉛也會增加MKP-1 mRNA含量及蛋白質的新合成。利用proteasome的抑制劑可減緩MKP-1被ubiquitination及分解的速率。PD98059會顯著抑制鉛誘發MKP-1的ubiquitination及分解，相反地，將含持續活化態MKK1/2的載體基因轉殖表達於哺乳類細胞會促使細胞內MKP-1的ubiquitination及分解。另外，轉殖表現具功能性的MKP-1於細胞內會降低鉛活化ERK1/2並增加細胞毒性。進而分析MKP-1蛋白質之胺基酸序列發現在278-286位置是一個能被ubiquitin-proteasome系統辨識之D box，且339-342位置含一個能與ERK1/2 結合的DEF模組及二個可能被ERK1/2磷酸化的絲胺酸(Ser296 and Ser323)。利用定點突變技術製備MKP-1突變蛋白質，發現D box及Ser296可能與MKP-1的分解有關。綜合上述，ERK1/2訊號傳遞路徑會將MKP-1磷酸化並促使ubiquitin-proteasome系統分解MKP-1，因而造成ERK1/2持久性地活化。

Abstract
Lead compounds are ubiquitous environmental contaminants that induce cellular transformations in cultured human cells and cancers in experimental rodents. Epidemiological studies suggest that lead exposure increases risk of lung, stomach, and bladder cancers in smelter or battery workers. Lead exhibits weak mutagenicity in mammalian cells and elicits signal transduction pathways in many aspects. To gain insight into the mechanism that lead-induced signal molecules affect genotoxicity, in this thesis, we investigated whether lead acetate (Pb(II)) could elicit four MAPKs and AKT to regulate DNA repair, cytotoxicity and mutagenicity in mammalian cells. We found that Pb(II) increases the phosphorylated-ERK1/2 and phosphorylated-AKT but not the phosphorylated-ERK5, phosphorylated-p38 and JNK activity in human non-small cell lung adenocarcinoma CL3 cells. The duration of ERK1/2 activation is much longer than AKT activation and these two signals are independently activated by Pb(II) in CL3 cells. Intriguingly, a MKK1/2 inhibitor PD98059 markedly blocks ERK1/2 activation and greatly promotes the hprt mutation frequency and cytotoxicity in CL3 cells as well as diploid human fibroblasts treated with Pb(II). Conversely, inhibition of the AKT signal by wortmannin does not exhibit such effects. Mannitol, a hydroxyl radical scavenger, blocks the ERK1/2 activation by Pb(II) and prevents the genotoxicity induced by Pb(II) in the presence of PD98059. The extent of Pb(II) genotoxicity is negative proportional to the cellular amounts of apurinic/apyridimic endonuclease (APE). In addition, Pb(II) increases the endonuclease activity of APE, which can be reduced by PD98059 co-treatment, suggesting that Pb(II)-activated ERK1/2 enhances cellular base excision repair (BER). The Pb(II)-induced genotoxicity is also significantly higher in nucleotide excision repair (NER)-deficient cells than their counterpart cells. Furthermore, cellular NER synthesis is enhanced by Pb(II) exposure, which is markedly suppressed by PD98059. Activation of ERK1/2 by expressing a constitutively active form of MKK1 in CL3 cells also elevates cellular NER synthesis. By using a cDNA microarray technique, we found that Pb(II) increases the expression of genes functioning in DNA repair, antioxidant, and metastasis in ERK1/2-dependent manner. Together, these results indicate that Pb(II) elevates cellular ROS resulting in genetic damage as well as activation of the sustained-ERK1/2, thereby triggering BER, NER and antioxidant systems to prevent cytotoxicity and mutagenicity, however, Pb(II)-elicited ERK1/2 may also promote metastasis.

We further investigated the mechanism by which sustained ERK1/2 activation is established by Pb(II). We demonstrated that the Ras-Raf-MKK1/2 signaling cannot fully account for the sustained ERK1/2 activation elicited by Pb(II). It is intriguing that Pb(II) treatment reduces MKP-1 protein levels in time- and dose-dependent manners, which correlates with sustained ERK1/2 activation, and that Pb(II) also induces mRNA and de novo protein synthesis of MKP-1. In Pb(II)-treated cells, MKP-1 is poly-ubiquitinated, and proteasome inhibitors markedly alleviate the ubiquitination and degradation of MKP-1. PD98059 greatly suppresses MKP-1 ubiquitination and degradation. Conversely, constitutive activation of MKK1/2 triggers endogenous MKP-1 ubiquitination and degradation. Furthermore, expression of functional MKP-1 decreases ERK1/2 activation and enhances cytotoxicity under Pb(II) exposure. Analysis of the MKP-1 amino acid sequence reveals that a D box to be recognized by ubiquitin-proteasome system located in position 278-286, and two putative ERK1/2 phosphorylation sites (Ser296 and Ser323) located upstream of the ERK1/2 docking, DEF motif (FXFP, 339-342). By using site-direct mutagenesis technique, we found that the D box and Ser296 may be correlated with MKP-1 degradation. Taken together, these results indicate that activated ERK1/2 can trigger MKP-1 phosphorylation and degradation via the ubiquitin-proteasome pathway, thus facilitating long-term activation of ERK1/2 against cytotoxicity.

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