DNA topoisomerase I is a cofactor for c-Jun in the regulation of epidermal growth factor receptor expression and cancer cell proliferation
DNA topoisomerase I is a cofactor for c-Jun in the regulation of epidermal growth factor receptor expression and cancer cell proliferation
复制标题
DOI：
10.1128/mcb.25.12.5040-5051.2005
复制
发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Westermarck, J
中科院分区：
文献类型：
--
作者：
Mialon, A;Sankinen, M;Westermarck, J
DNA拓扑异构酶I （Topo 1）是抗癌药物拓扑替康治疗小细胞肺癌和卵巢癌的分子靶点。然而，拓扑替康治疗抑制癌细胞增殖的分子机制尚不清楚。我们在这里描述了Topo I作为转录因子c-Jun的一种新的内源性相互作用伙伴的鉴定。互反共免疫沉淀分析显示，Topo I和c-Jun在转化的人细胞中以依赖于JNK活性的方式相互作用。c-Jun靶基因表皮生长因子受体（epidermal growth factor receptor， EGFR）是拓扑替康特异性抑制其表达的新基因。此外，Topo I过表达支持c-Jun介导的报告基因激活，以及c-Jun转化细胞对拓扑替康诱导的EGFR下调的遗传和化学抑制。拓扑替康诱导的增殖抑制被外源性表达的EGFR所挽救。此外，我们还证明了JNK-c-Jun通路、Topo I和EGFR在HT-1080细胞增殖的正向调节中的合作作用。总之，这些结果已经确定转录辅激活因子Topo I是c-Jun调控细胞增殖的第一个内源性辅因子。此外，本研究结果强烈提示，抑制EGFR表达是拓扑替康在癌症治疗中抑制细胞增殖的新机制。
DNA topoisomerase I (Topo 1) is a molecular target for the anticancer agent topotecan in the treatment of small cell lung cancer and ovarian carcinomas. However, the molecular mechanisms by which topotecan treatment inhibits cancer cell proliferation are unclear. We describe here the identification of Topo I as a novel endogenous interaction partner for transcription factor c-Jun. Reciprocal coimmunoprecipitation analysis showed that Topo I and c-Jun interact in transformed human cells in a manner that is dependent on JNK activity. c-Jun target gene epidermal growth factor receptor (EGFR) was identified as a novel gene whose expression was specifically inhibited by topotecan. Moreover, Topo I overexpression supported c-Jun-mediated reporter gene activation and both genetic and chemical inhibition of c-Jun converted cells resistant to topotecan-elicited EGFR downregulation. Topotecan-elicited suppression of proliferation was rescued by exogenously expressed EGFR. Furthermore, we demonstrate the cooperation of the JNK-c-Jun pathway, Topo I, and EGFR in the positive regulation of HT-1080 cell proliferation. Together, these results have identified transcriptional coactivator Topo I as a first endogenous cofactor for c-Jun in the regulation of cell proliferation. In addition, the results of the present study strongly suggest that inhibition of EGFR expression is a novel mechanism by which topotecan inhibits cell proliferation in cancer therapy.