Kitagawa Takao, Hashizume Yuko, Murakane Tatsuhiko, Koga Emi, Nomura Yuki, Kakihara Yoshito, Fujieda Ayako, Uchida Motoyuki, Takahashi Hidetoshi, Hoshida Hisashi, Akada Rinji
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Biosci Biotechnol Biochem. 2007 Mar;71(3):772-82. doi: 10.1271/bbb.60610. Epub 2007 Mar 7.
The yeast MAPKKK Ste11 activates three MAP kinase pathways, including pheromone signaling, osmosensing, and pseudohyphal/invasive growth pathways. We identified two chemical compounds, BTB03006 and GK03225, that suppress growth defects induced by Ste11 activation in diploid yeast cells. BTB03006, but not GK03225, was found to suppress growth defects induced by both alpha-factor and Ste4 G(beta) overexpression in the pheromone signaling pathway, suggesting that GK03225 is an osmosensing pathway-specific inhibitor. We also performed genome-wide suppressor analysis for Ste11 activation, using a yeast deletion strains collection, and identified PBS2 and HOG1, and several genes associated with chaperone functions, which represent potential target proteins of the drugs screened from Ste11 activation. GK03225 possesses an Iressa-like quinazoline ring structure, and its chemical analog, 11N-078, suppresses c-Abl human tyrosine kinase activity. These results suggest that drug screening in yeast can identify human tyrosine kinase inhibitors and other drugs for human diseases.
酵母丝裂原活化蛋白激酶激酶激酶（MAPKKK）Ste11可激活三条丝裂原活化蛋白激酶途径，包括信息素信号传导途径、渗透感应途径以及假菌丝/侵袭性生长途径。我们鉴定出两种化合物，BTB03006和GK03225，它们可抑制二倍体酵母细胞中由Ste11激活所诱导的生长缺陷。研究发现，BTB03006而非GK03225可抑制信息素信号传导途径中由α-因子和Ste4 Gβ过表达所诱导的生长缺陷，这表明GK03225是一种渗透感应途径特异性抑制剂。我们还利用酵母缺失菌株文库对Ste11激活进行了全基因组抑制子分析，鉴定出PBS2和HOG1，以及几个与伴侣功能相关的基因，它们代表了从Ste11激活筛选出的药物的潜在靶蛋白。GK03225具有类似易瑞沙的喹唑啉环结构，其化学类似物11N-078可抑制c-Abl人酪氨酸激酶活性。这些结果表明，在酵母中进行药物筛选可鉴定出人类酪氨酸激酶抑制剂及其他用于治疗人类疾病的药物。
