title: Anti-apoptotic roles for the mutant p53R248Q through suppression of p53-regulated apoptosis-inducing protein 1 in the RA-derived fibroblast-like synoviocyte cell line MH7A.
abstract: We previously reported that somatic mutations in the p53 gene accumulated at a higher frequency in AID(activation induced cytidine deaminase)(+) RA-FLS, which may result in the malfunction of p53, causing the tumor-like properties of RA-FLS. Among the p53 mutations identified from 3 sources of AID(+) RA-FLS, we focused on the p53R248Q mutation because it was reported to enhance the invasiveness of lung cancer cells and to have dominant-negative activity for pro-apoptotic molecules. We obtained cDNA encoding the p53R248Q mutant and introduced it into the MH7A RA-FLS cell line. P53R248Q dramatically suppressed the expression of the pro-apoptotic molecule p53AIP1 even under oxidative stress, which normally upregulates p53AIP1, leading to apoptosis. Moreover, overexpression of p53AIP1 increased apoptosis, whereas p53AIP1 knockdown rescued the cells from apoptosis. Together, these studies indicate the critical role of p53AIP1 under DNA damaging stresses for cell fate determination in RA-FLS containing the p53R248Q mutation.
authors: Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan.
authors: Hideya
authors: H
authors: Igarashi
authors: Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan.
authors: Hiroyasu
authors: H
authors: Hirano
authors: Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan.
authors: Ayano
authors: A
authors: Yahagi
authors: Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan.
authors: Taro
authors: T
authors: Saika
authors: Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Electronic address: ishihara-im@med.kawasaki-m.ac.jp.
authors: Katsuhiko
authors: K
authors: Ishihara
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001172:Arthritis, Rheumatoid; D002460:Cell Line; D005347:Fibroblasts; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009154:Mutation; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D013583:Synovial Membrane / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D016877:Oxidants; C414742:P53AIP1 protein, human; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide
keywords: AID; Apoptosis; Autoimmunity; FLS; H(2)O(2); Molecular immunology; RA; activation induced cytidine deaminase; fibroblast-like synoviocytes; hydrogen peroxide; rheumatoid arthritis.