Namba Takushi, Ishihara Tomoaki, Tanaka Ken-ichiro, Hoshino Tatsuya, Mizushima Tohru
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Biochem Biophys Res Commun. 2007 Apr 6;355(2):543-8. doi: 10.1016/j.bbrc.2007.02.004. Epub 2007 Feb 8.
Previous studies have shown that modification of activating transcription factor 6 (ATF6) protein is important for the endoplasmic reticulum (ER) stress response; ER stressors stimulate the degradation of ATF6 by Site-1 protease (S1P) and Site-2 protease (S2P) into p50-ATF6, which acts as a transcription factor. In the current study, we found that all of the ER stressors tested (such as thapsigargin) up-regulate ATF6 mRNA expression. As thapsigargin did not affect the stability of the ATF6 mRNA, it was concluded that this up-regulation is due to transcriptional activation of ATF6. An inhibitor of S1P suppressed this up-regulation of ATF6 mRNA expression and putative ATF6-binding elements in the promoter of ATF6 were identified, suggesting that p50-ATF6 positively regulates the gene expression of ATF6. Since cells over-expressing ATF6 showed an enhanced ER stress response, we propose that up-regulation of ATF6 mRNA expression is involved in enhancing the ER stress response.
先前的研究表明，激活转录因子6（ATF6）蛋白的修饰对于内质网（ER）应激反应很重要；ER应激源通过位点1蛋白酶（S1P）和位点2蛋白酶（S2P）刺激ATF6降解为p50-ATF6，p50-ATF6作为一种转录因子发挥作用。在当前研究中，我们发现所有测试的ER应激源（如毒胡萝卜素）均上调ATF6 mRNA表达。由于毒胡萝卜素不影响ATF6 mRNA的稳定性，因此得出结论，这种上调是由于ATF6的转录激活所致。S1P抑制剂抑制了ATF6 mRNA表达的这种上调，并鉴定了ATF6启动子中假定的ATF6结合元件，表明p50-ATF6正向调节ATF6的基因表达。由于过表达ATF6的细胞显示出增强的ER应激反应，我们提出ATF6 mRNA表达的上调参与增强ER应激反应。
