title: Proapoptotic action of p53-Tom5 in p53-resistant A549 human non-small cell lung cancer cells through direct mitochondrial dysfunction.
abstract: Transcription-dependent apoptosis triggered by p53 hardly occurs in alternative reading frame (ARF)-null cancer cells. Loss of ARF leads to hyperactivation of murine double minute 2 (MDM2), resulting in the degradation of p53. In the present study, A549 (ARF-null) human non-small lung cancer cells were transfected with a plasmid DNA encoding human wild-type p53 and the mitochondrial transmembrane domain of Tom5 (p53-Tom5) for delivering p53 to mitochondria. As a result, p53-Tom5 exclusively localized at mitochondria in A549 cells and suppressed the proliferation of them, whereas wild-type p53 did not. In addition, mitochondrial dysfunction and release of cytochrome c were induced by p53-Tom5 in A549 cells. These data suggest that p53-Tom5 suppressed the proliferation of A549 cells through direct mitochondrial dysfunction.
authors.affiliation: Department of Medical Biochemistry, Global COE Program, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Yada, Suruga-ku, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Umemoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.forename: Koji
authors.initials: K
authors.lastname: Hirashima
authors.forename: Kosuke
authors.initials: K
authors.lastname: Shimizu
authors.forename: Motohiro
authors.initials: M
authors.lastname: Mihara
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Koji
authors.initials: K
authors.lastname: Kubota
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D017209:Apoptosis; D001692:Biological Transport; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002352:Carrier Proteins / Q000627:therapeutic use*; D049109:Cell Proliferation; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA; D019008:Drug Resistance, Neoplasm; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D026901:Membrane Transport Proteins / Q000378:metabolism / Q000627:therapeutic use*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000627:therapeutic use*; D010957:Plasmids; D016364:Reading Frames; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; C568355:TOMM5 protein, human; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; D004247:DNA