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

Ling Lin; Toshinori Ozaki; Yuki Takada; Hajime Kageyama; Yoko Nakamura; Akira Hata; Jian-Hua Zhang; William F Simonds; Akira Nakagawara; Haruhiko Koseki

doi:10.1038/sj.onc.1208554

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

Oncogene. 2005 May 12;24(21):3385-96. doi: 10.1038/sj.onc.1208554.

Authors

Ling Lin¹, Toshinori Ozaki, Yuki Takada, Hajime Kageyama, Yoko Nakamura, Akira Hata, Jian-Hua Zhang, William F Simonds, Akira Nakagawara, Haruhiko Koseki

Affiliation

¹ Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

PMID: 15735665
DOI: 10.1038/sj.onc.1208554

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antineoplastic Agents / toxicity
Antineoplastic Agents, Phytogenic / toxicity
Apoptosis / genetics*
Bone Neoplasms / pathology
Camptothecin / toxicity
Carrier Proteins / genetics*
Carrier Proteins / pharmacology*
Cell Cycle
Cisplatin / toxicity
DNA Damage*
DNA Topoisomerases, Type I
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / pharmacology*
Gene Expression Regulation*
Genes, Tumor Suppressor
Humans
Mice
Molecular Sequence Data
Neoplasm Proteins / genetics*
Neoplasm Proteins / pharmacology*
Neoplasms / genetics
Neoplasms / physiopathology
Nuclear Proteins / genetics*
Nuclear Proteins / pharmacology*
Osteosarcoma / pathology
Promoter Regions, Genetic
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / genetics*
Transcription Factors / pharmacology*
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / biosynthesis*
Tumor Suppressor Protein p53 / pharmacology*
Ubiquitin-Protein Ligases
Zinc Fingers

Substances

Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Carrier Proteins
DNA-Binding Proteins
Neoplasm Proteins
Nuclear Proteins
Transcription Factors
Tumor Suppressor Protein p53
TOPORS protein, human
Ubiquitin-Protein Ligases
DNA Topoisomerases, Type I
Cisplatin
Camptothecin