The topoisomerase I- and p53-binding protein topors is differentially expressed in normal and malignant human tissues and may function as a tumor suppressor

Abstract

Topors was identified recently as a human protein that binds to topoisomerase I and p53. Topors contains a highly conserved RING domain and localizes in promyelocytic leukemia nuclear bodies. Relatively little is known regarding topors expression patterns or function. We now demonstrate that topors mRNA and protein are widely expressed in normal human tissues. By contrast, topors mRNA and protein levels are decreased or undetectable in colon adenocarcinomas relative to normal colon tissue, and expression of the topors protein is not detectable in several colon cancer cell lines. The human TOPORS gene is located on chromosome 9p21, with loss of heterozygosity in this region frequently observed in several different malignancies. While we were unable to detect loss of heterozygosity of the TOPORS gene in 16 sporadic colon cancer cases, increased methylation of a CpG island in the TOPORS promoter was evident in colon adenocarcinoma specimens relative to matched normal tissues. Additional studies indicate that forced expression of topors inhibits cellular proliferation and is associated with an accumulation of cells in the G 0 /G 1 phase of the cell cycle. This effect is independent of the topors RING domain and maps to a C-terminal region of the protein. These results suggest that topors functions as a negative regulator of cell growth, and possibly as a tumor suppressor.

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

“…Therefore, topors could affect the stability of p53 via covalent modification of p53 by ubiquitin isopeptide. This observation, however, is not necessarily consistent with our and others' previous observations suggesting topors as a likely tumor suppressor protein since polyubiquitination of p53 mediated by GFPtopors induces proteasome-dependent downregulation of p53 in U2-OS cells (Chu et al, 2001;Rajendra et al, 2004;Saleem et al, 2004). This implies that regulation of p53 by topors may involve not only ubiquitination but also some other molecular mechanism.…”

“…While this manuscript was in preparation, Saleem et al (2004) also reported that transient expression of h-topors showed antiproliferative activity and was associated with G0/G1 cell cycle arrest in HeLa cells. Our results additionally show that overexpression of topors could activate the expression of p53 and induce either cell cycle arrest or apoptotic response.…”

Ubiquitination by TOPORS Regulates the Prostate Tumor Suppressor NKX3.1

“…However, TOPORS maps to chromosome 9p21 and is located between microsatellite markers D9S270 and D9S273, which show loss of heterozygosity in 21.8 and 13.8% of prostate cancer samples examined, respectively (37). In addition, TOPORS protein has been shown to be diminished in colon cancer, where it may have tumor suppressor function (24). TOPORS has also been implicated as a tumor suppressor in human gliomas and non-small cell lung cancers (38,39).…”

“…Topoisomerase I is thought to interact with the RING domain-containing protein TOPORS (21), which is known to interact with the tumor suppressor p53 (22) and later was found to ubiquitinate p53 (23). TOPORS is widely expressed in various tissues including the prostate (24 …”

Epigenetic therapy in gastrointestinal cancer: the right combination

“…These include UGT1A1 and HNF1, which are involved in irinotecan elimination and display increased expression in irinotecan-resistant cell lines [Gagnon et al 2006;Bélanger et al 2010], TOPORS, which is involved in topoisomerase I and p53-binding [Saleem et al 2004], and DEXI, which is hypermethylated and showed demethylation with improved response to irinotecan after DAC treatment [Miyaki et al 2012]. Conversely, there was decreased sensitivity to irinotecan when DEXI was silenced with siRNA [Miyaki et al 2012].…”