金屬硫蛋白（MT）是個多功能性的蛋白質，其分子量小但具有高含量的半胱胺酸及金屬含量。MT的生物功能包括重金屬解毒、維持體內的金屬恆定、清除自由基等作用。此外MT也會參與在許多重要的生理過程中，例如細胞的增生或凋亡。當我們利用MT基因高度擴增的細胞株CdR來進行MT的相關研究時，可以發現到更換新鮮培養液會造成MT之基礎表現量增加，而在新鮮培養液中唯有NaHCO3會隨劑量的增加誘導MT基因之表現。在我們研究中也發現，其他可以增加培養液之pH值的藥品，如HEPES、NaOH及KOH等，同樣具有刺激MT表現的能力。當我們利用MT啟動子-luciferase報導基因，探討NaHCO3誘導MT基因表現的機制時，發現必須有啟動子區域之金屬反應序列（MRE）的存在才能進行轉錄作用。同時NaHCO3也會促使轉錄因子MTF-1進入細胞核內，並增加其與金屬反應序列之結合能力。
為了進一步探討NaHCO3刺激MT基因表現之調控機制，我們以還原劑GSH、DTT、cysteine或NAC與NaHCO3共同處理，結果發現MT的誘導表現會受到抑制，反之當以氧化劑GSSG或DTNB與NaHCO3共同處理時，則不影響MT的誘導表現。而且處理NaHCO3時所增加的游離態之鋅離子及MTF-1與DNA的結合活性，同樣也會受到氧化劑與還原劑的影響。此外，當我們處理NaHCO3時，也可以觀察到細胞內的ROS及ATP量的增加，並且會降低細胞內的GSH含量，代表細胞內的氧化還原狀態會被NaHCO3所影響。綜合上述，我們知道NaHCO3會藉由影響細胞內的pH值及氧化還原的衡定，刺激細胞內鋅離子的移動並活化MTF-1，影響到MT基因的表現。
我們也探討了NaHCO3誘導MT基因表現之生理意義。由結果可以發現到，以NaHCO3處理細胞可以加速CdR細胞週期的進行並造成細胞的增生，卻不能影響到其來源母細胞CHO K1細胞的生長。CHO K1細胞之啟動子區域被甲基化而無法表現MT基因，但當我們在CHO K1細胞中以轉殖方式表現MT蛋白質，或是將細胞處理5-azacytidine（Aza）使MT啟動子區域的甲基被去除，以表現其內生性的MT時，即可以增加CHO K1細胞的生長。此外，當CHO K1細胞處理基因去甲基化之藥劑後再加入NaHCO3時，也可誘導細胞表現MT並促進增生，代表NaHCO3刺激細胞增生必須透過MT。

Metallothionein (MT) gene expression is increased in cadmium resistant Chinese hamster ovary cells (CHO CdR) upon medium (regular or serum-free) change during culturing. Among the major components of the medium, NaHCO3 was found to be able to induce MT gene expression in a dose- and time-dependent manner. The same effect was observed with other alkaline solutions, such as HEPES and NaOH. Moreover, NaHCO3 express caused the increase of cytosolic free zinc without change of total cellular zinc content, which means that the increase of zinc is released from intracellular storage. Using MT promoter-luciferase reporter gene constructs, we found that the presence of metal response elements (MREs) in the promoter region is necessary for NaHCO3-induced MT gene transcription. This finding is further supported by the observation that the binding activity between the metal-responsive transcription factor 1 (MTF-1) and the MRE were increased after NaHCO3 treatment. When CdR cells were treated with NaHCO3 in the present of the reduced thiol reagents (glutathione, dithiothreitol, cysteine or N-acetylcysteine), MT expression was reduced. On the contrary, giving oxidized thiol reagents (GSSG or 5,5-dithiobis-2-nitrobenzoic acid) had no influence on the NaHCO3-induced MT gene expression. The reduced thiol reagents apparently inhibit the release of intracellular free zinc and MTF-1 DNA binding activity that results in a reduction of MT gene expression. NaHCO3 treatment increased the intracellular reactive oxygen species and ATP level but decreased glutathione content. These results suggest that cellular alkalinization disturbs thiol redox status and increases the cytosolic zinc, which causes the MTF-1 activation and the MT gene expression. Following NaHCO3 treatment, an increase in cell proliferation was observed in CdR cells but not in the parental CHO K1 cells that do not express MT transcripts due to MT gene methylation. Using synchronized cells, an increase in cell proliferation was observed 9 h after NaHCO3 addition. Notably, proliferation of CHO K1 cells was increased when transfected with an MT gene. The effect of MT on cell growth was affirmed by treating CHO K1 cells with 5-azacytidine (Aza) to demethylate the MT gene. Proliferation increased in Aza-treated CHO K1 cells after NaHCO3 treatment. These results demonstrate that NaHCO3-induced MT gene expression causes an enhancement of cell proliferation in CHO cells.

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