title: Expression and mutation analyses of P53R2, a newly identified p53 target for DNA repair in human gastric carcinoma.
abstract: p53R2, a recently identified putative tumor suppressor located at 8q23.1, encodes a protein with striking similarity to a small subunit of ribonucleotide reductase. p53R2 is directly induced by wild-type p53 and involved in the p53 checkpoint for repair of damaged DNA, raising the possibility that mutational inactivation of p53R2 may contribute to the development and progression of human malignancies. To explore the p53R2's candidacy for a suppressor in gastric tumorigenesis, we examined the expression and mutation status of p53R2 in 166 gastric specimens including 90 primary adenocarcinomas and 15 cell lines. In response to genotoxic damages, p53R2 transcription was clearly activated in wild-type but not mutant-type p53-carrying cells while basal expression of p53R2 in undamaged cells showed no association with the mutational status of p53. Host cell reactivation assay revealed that p53R2 enhances DNA repair efficiency and plays a role in the p53-mediated repair of damaged DNA, whereas no significant effect of p53R2 on cell growth and apoptosis was detected in flow cytometry and [(3)H]thymidine incorporation assays. p53R2 transcript was expressed in all normal and tumor tissues and its expression levels were not significantly different between normal and malignant carcinoma tissues. p53R2 expression showed no correlation with stage, grade and histological types of tumors. Moreover, no tumor-specific reduction of p53R2 was detected in 30 matched sets. Mutational analysis of p53R2 in 105 carcinomas including 15 cell lines also failed to detect any evidences for genomic deletion or somatic mutations leading to amino acid substitutions or frameshift whereas 31% (28 of 90) of the same primary tumors showed p53 alterations. Whereas 82% (23 of 28) of the mutant p53-carrying primary tumors expressed abnormally low p21(Waf1), no association of p53R2 expression with the p53 status was recognized, suggesting that basal transcription of p53R2 is regulated through the p53-independent mechanism. Collectively, our study indicates that although p53R2 is induced in a p53-dependent manner and involved the p53-mediated DNA repair in gastric epithelial cells, it is not a critical target of genetic inactivation in gastric tumorigenesis.
authors.affiliation: Department of Pathology, College of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Do-Sun
authors.initials: DS
authors.lastname: Byun
authors.forename: Kwon-Seok
authors.initials: KS
authors.lastname: Chae
authors.forename: Byung-Kyu
authors.initials: BK
authors.lastname: Ryu
authors.forename: Min-Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Sung-Gil
authors.initials: SG
authors.lastname: Chi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000032:analysis; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases