title: NF2 blocks Snail-mediated p53 suppression in mesothelioma.
abstract: Although asbestos causes malignant pleural mesothelioma (MPM), rising from lung mesothelium, the molecular mechanism has not been suggested until now. Extremely low mutation rate in classical tumor suppressor genes (such as p53 and pRb) and oncogenes (including Ras or myc) indicates that there would be MPM-specific carcinogenesis pathway. To address this, we treated silica to mimic mesothelioma carcinogenesis in mesothelioma and non-small cell lung cancer cell lines (NSCLC). Treatment of silica induced p-Erk and Snail through RKIP reduction. In addition, p53 and E-cadherin were decreased by silica-treatment. Elimination of Snail restored p53 expression. We found that NF2 (frequently deleted in MPM) inhibited Snail-mediated p53 suppression and was stabilized by RKIP. Importantly, GN25, an inhibitor of p53-Snail interaction, induced p53 and apoptosis. These results indicate that MPM can be induced by reduction of RKIP/NF2, which suppresses p53 through Snail. Thus, the p53-Snail binding inhibitor such as GN25 is a drug candidate for MPM.
authors.affiliation: Department of Molecular Biology, Graduated School of System Biology, College of Natural Science, Pusan National University, Busan.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Department of Molecular Biology, Graduated School of System Biology, College of Natural Science, Pusan National University, Busan.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, Graduated School of System Biology, College of Natural Science, Pusan National University, Busan.
authors.forename: Ah-Young
authors.initials: AY
authors.lastname: Oh
authors.affiliation: Department of Molecular Biology, Graduated School of System Biology, College of Natural Science, Pusan National University, Busan.
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Yoon
authors.affiliation: Department of Molecular Biology, Graduated School of System Biology, College of Natural Science, Pusan National University, Busan.
authors.forename: Tae-Geun
authors.initials: TG
authors.lastname: Woo
authors.affiliation: Department of Molecular Biology, Graduated School of System Biology, College of Natural Science, Pusan National University, Busan.
authors.forename: Bum-Joon
authors.initials: BJ
authors.lastname: Park
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008654:Mesothelioma / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000086002:Mesothelioma, Malignant; D009285:Naphthoquinones / Q000494:pharmacology; D025581:Neurofibromin 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism; D012822:Silicon Dioxide / Q000633:toxicity; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C587449:GN25 compound; D009285:Naphthoquinones; D025581:Neurofibromin 2; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D000071250:Snail Family Transcription Factors; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D012822:Silicon Dioxide; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: NF2; RKIP; Snail; mesothelioma; p53
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