Ueda Koji, Arakawa Hirofumi, Nakamura Yusuke
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Oncogene. 2003 Aug 28;22(36):5586-91. doi: 10.1038/sj.onc.1206845.
Dual-specificity phosphatase 5 (DUSP5), a VH1-like enzyme that hydrolyses nuclear substrates phosphorylated on both tyrosine and serine/threonine residues, has a potential role in deactivation of mitogen- or stress-activated protein kinases. Using cDNA-microarray technology, we found that the expression of DUSP5 mRNA was dramatically increased by exogenous p53 in U373MG, a p53-mutant glioblastoma cell line. Transcription of DUSP5 was also remarkably activated by endogenous p53 in response to DNA damage in colon-cancer cells (p53+/+) that contained wild-type p53, but not in p53-/- cells. Chromatin-immunoprecipitation (ChIP) and reporter assays demonstrated that endogenous p53 protein would bind directly to the promoter region of the DUSP5 gene, implying p53-dependent transcriptional activity. Overexpression of DUSP5 suppressed the growth of several types of human cancer cells, in which Erk1/2 was significantly dephosphorylated. If, as the results suggest, DUSP5 is a direct target of p53, it represents a novel mechanism by which p53 might negatively regulate cell-cycle progression by downregulating mitogen- or stress-activated protein kinases.
双特异性磷酸酶5（DUSP5）是一种VH1样酶，可水解在酪氨酸和丝氨酸/苏氨酸残基上均被磷酸化的核底物，在丝裂原或应激激活的蛋白激酶失活中具有潜在作用。利用cDNA微阵列技术，我们发现，在p53突变的胶质母细胞瘤细胞系U373MG中，外源性p53可使DUSP5 mRNA的表达显著增加。在含有野生型p53的结肠癌细胞（p53+/+）中，内源性p53也可在DNA损伤时显著激活DUSP5的转录，但在p53-/-细胞中则不然。染色质免疫沉淀（ChIP）和报告基因检测表明，内源性p53蛋白可直接结合到DUSP5基因的启动子区域，这意味着存在p53依赖性转录活性。DUSP5的过表达抑制了几种类型的人类癌细胞的生长，其中Erk1/2被显著去磷酸化。如果正如结果所示，DUSP5是p53的直接靶点，那么它代表了一种新的机制，通过该机制p53可能通过下调丝裂原或应激激活的蛋白激酶来负向调节细胞周期进程。
