De Nadal Eulàlia, Zapater Meritxell, Alepuz Paula M, Sumoy Lauro, Mas Glòria, Posas Francesc
Cell Signaling Unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, E-08003 Barcelona, Spain.
Nature. 2004 Jan 22;427(6972):370-4. doi: 10.1038/nature02258.
Regulation of gene expression by mitogen-activated protein kinases (MAPKs) is essential for proper cell adaptation to extracellular stimuli. Exposure of yeast cells to high osmolarity results in rapid activation of the MAPK Hog1, which coordinates the transcriptional programme required for cell survival on osmostress. The mechanisms by which Hog1 and MAPKs in general regulate gene expression are not completely understood, although Hog1 can modify some transcription factors. Here we propose that Hog1 induces gene expression by a mechanism that involves recruiting a specific histone deacetylase complex to the promoters of genes regulated by osmostress. Cells lacking the Rpd3-Sin3 histone deacetylase complex are sensitive to high osmolarity and show compromised expression of osmostress genes. Hog1 interacts physically with Rpd3 in vivo and in vitro and, on stress, targets the deacetylase to specific osmostress-responsive genes. Binding of the Rpd3-Sin3 complex to specific promoters leads to histone deacetylation, entry of RNA polymerase II and induction of gene expression. Together, our data indicate that targeting of the Rpd3 histone deacetylase to osmoresponsive promoters by the MAPK Hog1 is required to induce gene expression on stress.
丝裂原活化蛋白激酶（MAPK）对基因表达的调控对于细胞正确适应细胞外刺激至关重要。将酵母细胞暴露于高渗透压环境会导致MAPK Hog1迅速激活，Hog1可协调细胞在渗透压胁迫下存活所需的转录程序。尽管Hog1可以修饰一些转录因子，但Hog1以及一般的MAPK调控基因表达的机制尚未完全明确。在此，我们提出Hog1通过一种机制诱导基因表达，该机制涉及将一种特定的组蛋白去乙酰化酶复合物招募到受渗透压胁迫调控的基因启动子上。缺乏Rpd3 - Sin3组蛋白去乙酰化酶复合物的细胞对高渗透压敏感，并且渗透压胁迫基因的表达受损。Hog1在体内和体外均与Rpd3发生物理相互作用，在应激状态下，将去乙酰化酶靶向特定的渗透压应激反应基因。Rpd3 - Sin3复合物与特定启动子的结合导致组蛋白去乙酰化、RNA聚合酶II的进入以及基因表达的诱导。总之，我们的数据表明，MAPK Hog1将Rpd3组蛋白去乙酰化酶靶向渗透压反应启动子是应激诱导基因表达所必需的。
