Department of Life Science and Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
Biochem J. 2012 Jan 1;441(1):367-77. doi: 10.1042/BJ20111257.
MTF-1 (metal-responsive transcription factor 1) is an essential mammalian protein for embryonic development and modulates the expression of genes involving in zinc homoeostasis and responding to oxidative stress. We report in the present paper that PTEN (phosphatase and tensin homologue deleted on chromosome 10) 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 MT (metallothionein) 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. Zinc increased MTF-1-PTEN interaction in a dose-dependent manner. The interaction elevated within 2 h of zinc addition and declined afterwards in the cells. The enhanced binding activity occurred mainly in the cytoplasm and reduced after translocating the MTF-1 into the nucleus. Blocking signalling through the PI3K (phosphoinositide 3-kinase) pathway did not alter the zinc-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. The same regulatory role of PTEN was also noted in the regulation of ZnT1 (zinc transporter 1), another target gene of MTF-1.
MTF-1（金属反应转录因子 1）是哺乳动物胚胎发育所必需的蛋白质，调节参与锌稳态和应对氧化应激的基因表达。本研究报告称，PTEN（染色体 10 上缺失的磷酸酶和张力蛋白同系物）与细胞中的 MTF-1 相关联。这两种蛋白质通过 MTF-1 的酸性结构域和 PTEN 的磷酸酶/C2 结构域相互作用。PTEN 耗竭降低了 MT（金属硫蛋白）基因的表达，并增加了细胞对镉毒性的敏感性。PTEN 没有改变 MTF-1 的核易位、蛋白质稳定性或 DNA 结合活性。锌以剂量依赖的方式增加 MTF-1-PTEN 相互作用。这种相互作用在锌添加后 2 小时内增加，并随后在细胞中减少。增强的结合活性主要发生在细胞质中，并在将 MTF-1 转移到细胞核后减少。阻断 PI3K（磷酸肌醇 3-激酶）途径的信号不改变锌诱导的 MT 表达。对酶失活的 PTEN 突变体的分析表明，PTEN 的蛋白而不是脂质磷酸酶活性参与了 MTF-1 活性的调节。PTEN 还在调节 MTF-1 的另一个靶基因 ZnT1（锌转运蛋白 1）方面发挥了相同的调节作用。
