Identification of a novel gene encoding a p53-associated protein

Zhou, Renchao; Wen, Hong; Ao, Shi-Zhou

doi:10.1016/s0378-1119(99)00203-6

Cited by 45 publications

(51 citation statements)

References 32 publications

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“…Our finding that topors mRNA is widely expressed in normal human tissues is consistent with previous reports (Zhou et al, 1999;Chu et al, 2001). Furthermore, similar to Zhou et al (1999), we observed high levels of topors mRNA in the testis. By contrast, we observed that topors mRNA levels are commonly decreased or undetectable in human colon adenocarcinomas.…”

Section: Discussionsupporting

confidence: 93%

“…Topors is a 1045-amino-acid protein that was originally discovered in a screen for proteins that bind to the Nterminus of topoisomerase I (Haluska et al, 1999), and was also identified in a screen for proteins that interact with p53 (denoted p53BP3) (Zhou et al, 1999). Furthermore, topors was identified in an assay for RING-domain proteins that are expressed in normal lung tissue (denoted LUN) (Chu et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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The yeast genes SLX5 and SLX8 were identified based on their requirement for viability in the absence of the Sgs1 DNA helicase. Loss of these genes results in genome instability, nibbled colonies, and other phenotypes associated with defects in sumoylation. The Slx5 and Slx8 proteins form a stable complex and each subunit contains a single RING-finger domain at its C-terminus. To determine the physiological function of the Slx5-8 complex, we explored its interaction with the SUMO pathway. Curing 2μ circle from the mutants suppressed their nibbled colony phenotype and partially improved their growth rate, but did not affect their sensitivity to hydroxyurea. The increase in sumoylation observed in slx5Δ and slx8Δ mutants was found to be dependent on the Siz1 SUMO ligase. Physical interactions between the Slx5-8 complex and both Ubc9 and Smt3 were identified and characterized. Using in vitro reactions, we show that Slx5, Slx8, or the Slx5-8 complex stimulates the formation of SUMO chains and the sumoylation of a test substrate. Interestingly, a functional RING-finger domain is not required for this stimulation in vitro. These biochemical data demonstrate for the first time that the Slx5-8 complex is capable of interacting directly with the SUMO pathway.

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“…Human topoisomerase I-binding protein (h-topors) was first identified by yeast two-hybrid screening as a protein that interacts with human topoisomerase I (hTop1), and turned out to be identical to a novel p53-binding protein, p53BP3 (Haluska et al, 1999;Zhou et al, 1999). An identical protein was also isolated as the DNA-binding protein LUN, as a protein that interacts with adeno-associated virus type 2 (AAV-2) Rep78/68 proteins and as a protein binding to the interferon-inducible large GTPase Mx1 (Chu et al, 2001;Engelhardt et al, 2001;Weger et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Although h-topors interacts with p53 as revealed by yeast two-hybrid assay, the role of h-topors in regulating the function of p53 remains to be clarified (Zhou et al, 1999;Weger et al, 2002). Several lines of evidence suggest that h-topors might be an important regulator in cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

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

Ozaki

Takada

et al. 2005

Oncogene

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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.

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Identification of a novel gene encoding a p53-associated protein

Cited by 45 publications

References 32 publications

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

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

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

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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