极光激酶A（AURKA）是胰腺癌中丝裂原活化蛋白激酶1/细胞外信号调节激酶2（MAPK1/ERK2）的下游靶点之一。

AURKA is one of the downstream targets of MAPK1/ERK2 in pancreatic cancer.

作者信息

Furukawa T, Kanai N, Shiwaku H O, Soga N, Uehara A, Horii A

机构信息

International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan.

出版信息

Oncogene. 2006 Aug 10;25(35):4831-9. doi: 10.1038/sj.onc.1209494. Epub 2006 Mar 13.

DOI:10.1038/sj.onc.1209494

PMID:16532023

Abstract

DUSP6/MKP-3, a specific inhibitor of MAPK1/ERK2, frequently loses its expression in primary pancreatic cancer tissues. This evidence suggests that constitutive activation of MAPK1 synergistically induced by frequent mutation of KRAS2 and the loss of function of DUSP6 plays key roles in pancreatic carcinogenesis and progression. By profiling of gene expressions associated with downregulation of MAPK1 induced by exogenous overexpression of DUSP6 in pancreatic cancer cells, we found that AURKA/STK15, the gene encoding Aurora-A kinase, which plays key roles in cellular mitosis, was among the downregulated genes along with its related genes, which included AURKB, TPX2 and CENPA. An association of expression and promoter activity of AURKA with MAPK activity was verified. Knockdown of ETS2 resulted in a reduction of AURKA expression. These results indicate that AURKA is a direct target of the MAPK pathway and that its overexpression in pancreatic cancer is induced by hyperactivation of the pathway, at least via ETS2.

摘要

双特异性磷酸酶6（DUSP6）/丝裂原活化蛋白激酶磷酸酶3（MKP-3）是丝裂原活化蛋白激酶1（MAPK1）/细胞外信号调节激酶2（ERK2）的特异性抑制剂，在原发性胰腺癌组织中常常表达缺失。这一证据表明，KRAS2频繁突变和DUSP6功能丧失协同诱导的MAPK1组成性激活在胰腺癌的发生和发展中起关键作用。通过对胰腺癌细胞中外源性过表达DUSP6诱导的MAPK1下调相关基因表达进行分析，我们发现，编码在细胞有丝分裂中起关键作用的极光激酶A（Aurora-A激酶）的基因AURKA/STK15与其相关基因（包括AURKB、TPX2和CENPA）一同属于下调基因。AURKA的表达和启动子活性与MAPK活性之间的关联得到了验证。敲低ETS2导致AURKA表达降低。这些结果表明，AURKA是MAPK途径的直接靶点，并且其在胰腺癌中的过表达至少通过ETS2由该途径的过度激活诱导产生。