topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage

Abstract

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.