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 myctagged 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.

Stimulation of in vitro sumoylation by Slx5–Slx8: Evidence for a functional interaction with the SUMO pathway

“…Precedent for such a dual-activity protein is provided by the conserved RING-finger protein, Topors. Topors binds DNA topoisomerase I [50] and p53 [51,52] and it displays both Ub E3 ligase [53,54] and SUMO ligase activity [55]. Topors Ub ligase activity is dependent on its RING-finger domain, while its SUMO ligase activity is not [55].…”

The ubiquitin–proteasome system regulates p53-mediated transcription at p21waf1 promoter

“…Topors have been shown to function as an E3 Ub ligase for p53 (Rajendra et al, 2004). Besides, topers can associate with p53 and act as a co-activator for p53 in growth suppression induced by DNA damage (Lin et al, 2005). These properties make topors a likely E3 Ub ligase candidate in the regulation of p53-mediated transcription by UPS.…”

“…More than half a dozen of E3 Ub ligases have shown to target p53 for proteolysis. However, most of E3s have inhibitory effect on p53-mediated transcription except for topors (topoisomerase I-binding protein) (Lin et al, 2005;Brooks and Gu, 2006). Topors have been shown to function as an E3 Ub ligase for p53 (Rajendra et al, 2004).…”

MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells

“…These factors include tumor protein p53 binding protein 2 (TP53BP2), topoisomerase I binding (TOPORS), junction-mediating and regulatory protein (JMY), heterogeneous nuclear ribonucleoprotein K (HNRPK), and death-associated protein 6 (DAXX; refs. [21][22][23][24][25][26]. A recent publication revealed a correlation between miR-21 and some transcripts that are up-regulated in response to p53 activation; however, they failed to determine the mechanism of interaction between miR-21 and p53 (15).…”

“…p53 pathway predicted targets included the tumor-suppressive homologue of p53, TP73L (TAp63), and activating cofactors of p53, such as JMY, TOPORS, HNRPK, and TP53BP2 (19,(21)(22)(23)(24)(25)(26). All the above genes are known to associate with p53 and assist in the transcriptional activation of antiproliferative and proapoptotic genes in response to DNA damage.…”