topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage.
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.
Lin
Ling
L
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Ozaki
Toshinori
T
Takada
Yuki
Y
Kageyama
Hajime
H
Nakamura
Yoko
Y
Hata
Akira
A
Zhang
Jian-Hua
JH
Simonds
William F
WF
Nakagawara
Akira
A
Koseki
Haruhiko
H
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D017209:Apoptosis / Q000235:genetics*; D001859:Bone Neoplasms / Q000473:pathology; D002166:Camptothecin / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics* / Q000494:pharmacology*; D002453:Cell Cycle; D002945:Cisplatin / Q000633:toxicity; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000494:pharmacology*; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000494:pharmacology*; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000494:pharmacology*; D012516:Osteosarcoma / Q000473:pathology; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases; D016335:Zinc Fingers
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C120157:TOPORS protein, human; D044767:Ubiquitin-Protein Ligases; D004264:DNA Topoisomerases, Type I; D002945:Cisplatin; D002166:Camptothecin