topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage
topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage
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DOI：
10.1038/sj.onc.1208554
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发表时间：
2005-05-12
期刊：
影响因子：
8
通讯作者：
Koseki, H
中科院分区：
文献类型：
--
作者：
Lin, L;Ozaki, T;Koseki, H
RING家族锌指蛋白topors（拓扑异构酶I结合蛋白）不仅结合拓扑异构酶I，而且结合p53和AAV-2 Rep 78/68蛋白。Topors定位于人类染色体9 p21，其中包含与小细胞肺癌有关的候选肿瘤抑制基因。在这项研究中，我们分离出小鼠对应的topors和研究其对p53功能的影响。小鼠topors的推导氨基酸序列与人类topors具有广泛的相似性。过表达的myc标记的topors与p53相关并稳定p53，增强p21（Waf 1）、MDM 2和Bax启动子的p53依赖性转录活性，并提高内源性p21（Waf 1）mRNA水平。因此，topors的过表达通过细胞周期停滞和/或通过诱导细胞凋亡而导致细胞生长的抑制。总之，这些研究将topors确定为p53的正调节剂。通过暴露于遗传毒性试剂顺铂和喜树碱（DNA拓扑异构酶I抑制剂）诱导topors的表达。因此，我们假设topors介导的p53依赖的DNA损伤诱导的细胞反应，这表明其作为一种肿瘤抑制剂的生理作用。
The RING family zinc-finger protein topors (topoisomerase I-binding protein) binds not only topoisomerase I, but also p53 and the AAV-2 Rep78/68 proteins. topors maps to human chromosome 9p21, which contains candidate tumor suppressor genes implicated in small cell lung cancers. In this study, we isolated the murine counterpart of topors and investigated its impact on p53 function. The deduced amino-acid sequence of mouse topors exhibits extensive similarity to human topors. Overexpressed myc-tagged topors associates with and stabilizes p53, and enhances the p53-dependent transcriptional activities of p21(Waf1), MDM2 and Bax promoters and elevates endogenous p21(Waf1) mRNA levels. Overexpression of topors consequently results in the suppression of cell growth by cell cycle arrest and/or by the induction of apoptosis. Taken together, these studies identify topors as a positive regulator of p53. The expression of topors is induced by exposure to the genotoxic reagents cisplatin and camptothecin, a DNA topoisomerase I inhibitor. We therefore postulate that topors mediates p53-dependent cellular responses induced by DNA damage, suggesting its physiological role as a tumor suppressor.