金屬感應轉錄因子(MTF-1)在哺乳類動物胚胎發育上是非常重要且必需的蛋白質，控制了多數細胞內鋅離子恆定以及抗氧化基因的表現。本篇研究中我們首次提出了PTEN與MTF-1具有交互作用，並分別藉由MTF-1的acidic domain與PTEN的phosphatase/C2 domain形成交互作用。當我們在細胞內大量表現PTEN時，會促進金屬硫蛋白(MT)的基因表現；反之我們利用siRNA將細胞中的PTEN 進行knockdown時，則會降低細胞中MT的基因表現，此時也導致細胞對於重金屬鎘毒性的敏感性增加。本篇的研究也指出PTEN無法影響MTF-1受金屬刺激後移動進入細胞核、蛋白質穩定性、與DNA結合的能力以及細胞對於金屬離子的吸收。
本篇研究發現細胞於鋅離子的刺激下，MTF-1與PTEN的交互作用將會增加，且該交互作用會隨著鋅離子的處理劑量逐漸升高而增強。鋅離子處理2個小時，PTEN與MTF-1的交互作用能力會達到最高值，而後隨著時間此交互作用將會下降而回到原來的基準值。我們也證實鋅離子刺激所造成交互作用增加的情形主要是發生在細胞質中，當MTF-1進入細胞核時該交互作用則有下降的情形，並且於鋅離子刺激下，PTEN並不存在於MT基因之啟動子上。
PTEN可以負向調控PI3K訊號傳遞的路徑，當我們利用抑制劑或藉由siRNA knockdown的方法阻斷此PI3K訊號傳遞路徑時，並沒有改變細胞受鋅刺激時所造成金屬硫蛋白基因大量表現的現象。藉由PTEN去磷酸化酵素活性突變的實驗結果，也證實了PTEN透過其蛋白質去磷酸化酵素活性調控MTF-1的轉錄活性，而非PTEN的脂質去磷酸化酵素活性。利用磷酸化酪胺酸抗體針對MTF-1的磷酸化狀態進行分析時，也發現PTEN的大量表現會降低MTF-1的酪胺酸磷酸化的修飾程度。最後本篇研究也證實PTEN會藉由相同的調控機制，調節另MTF-1的另一個下游基因，ZnT 1的基因表現。
本篇研究中我們提出了一個全新且具有顯著細胞生理意義的MTF-1活性調控機制，說明了腫瘤抑制因子PTEN會與MTF-1進行交互作用，並且藉由其蛋白質去磷酸化酵素作用而影響MTF-1的轉錄活性。

Metal-responsive transcription factor 1 (MTF-1) is an essential mammalian protein for embryonic development and modulates the expression of genes involving in Zn homeostasis and responding to oxidative stress. We report here that phosphatase and tensin homologue deleted on chromosome 10 (PTEN) associates with MTF-1 in the cells. These two proteins interact via the acidic domain of MTF-1 and the phosphatase/C2 domain of PTEN. Depletion of PTEN reduced metallothionein (MT) gene expression and increased cellular sensitivity to cadmium toxicity. PTEN did not alter the nuclear translocation, protein stability or DNA-binding activity of MTF-1 and cellular absorption of metal ions. Zn increased MTF-1/PTEN interaction in a dose-dependent manner. The interaction elevated within 2 h of Zn addition and declined afterward in the cells. The enhanced binding activity occurred mainly in cytoplasm and reduced after translocating the MTF-1 into nucleus. In addition, PTEN had not been recruited in MT promoter upon Zinc exposure. Blocking signalling through the phosphatidylinositol 3-kinase pathway did not alter the Zn-induced MT expression. Analysis of enzymatically inactive PTEN mutants demonstrated that protein but not lipid phosphatase activity of PTEN was involved in the regulation of MTF-1 activity. Elevation of PTEN expression reduced the phosphorylation level of MTF-1 as recognized by anti-phosphotyrosine antibody. The same regulatory role of PTEN was also noted in the regulation of Zn transporter 1, another target gene of MTF-1. Our results reveal a novel mode of regulation for MTF-1.

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