title: Nuclear and cytoplasmic p53 suppress cell invasion by inhibiting respiratory complex-I activity via Bcl-2 family proteins.
abstract: Although the p53 tumor suppressor/transcription factor often accumulates in the cytoplasm of healthy cells, limited information is available on the cytoplasmic function of p53. Here, we show that cytoplasmic p53 suppresses cell invasion by reducing mitochondrial reactive oxygen species (ROS) levels. Analysis revealed that this function is mediated by Bcl-2 family proteins: Cytoplasmic p53 binds Bcl-w, liberating Bax, which then binds ND5, a subunit of respiratory complex-I, thereby suppressing complex-I activity and thus ROS production. The G13289A mutation of ND5, identified in cancer patients, prevents Bax/ND5 interactions and promotes ROS production and cell invasion. We also showed that Bcl-XL and Bak can substitute for Bcl-w and Bax, respectively, regulating complex-I activity and supporting the cytoplasmic function of p53; nuclear p53 also suppresses complex-I activity by inducing Bax expression. Studies in animal models support the notion that p53 and Bcl-2 family proteins exhibit these functions in vivo. This study demonstrates a link between p53 and Bcl-2 proteins as regulators of ROS production and cellular invasiveness, and reveals complex-I, especially ND5, as their functional target.
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea; Division of Life and Pharmaceutical Science, Ewha Woman's University Seoul, Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Kim
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.affiliation: Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea.
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zheng-Gang
authors.initials: ZG
authors.lastname: Liu
authors.affiliation: Division of Life and Pharmaceutical Science, Ewha Woman's University Seoul, Korea.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C491073:BCL2L2 protein, human; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C481838:MT-ND5 protein, human; D042967:Electron Transport Complex I