title: Regulation of Noxa-mediated apoptosis in Helicobacter pylori-infected gastric epithelial cells.
abstract: Helicobacter pylori induces the antiapoptotic protein myeloid cell leukemia 1 (Mcl1) in human gastric epithelial cells (GECs). Apoptosis of oncogenic protein Mcl1-expressing cells is mainly regulated by Noxa-mediated degradation of Mcl1. We wanted to elucidate the status of Noxa in H. pylori-infected GECs. For this, various GECs such as AGS, MKN45, and KATO III were either infected with H. pylori or left uninfected. The effect of infection was examined by immunoblotting, immunoprecipitation, chromatin immunoprecipitation assay, in vitro binding assay, flow cytometry, and confocal microscopy. Infected GECs, surgical samples collected from patients with gastric adenocarcinoma as well as biopsy samples from patients infected with H. pylori showed significant up-regulation of both Mcl1 and Noxa compared with noninfected samples. Coexistence of Mcl1 and Noxa was indicative of an impaired Mcl-Noxa interaction. We proved that Noxa was phosphorylated at Ser(13) residue by JNK in infected GECs, which caused cytoplasmic retention of Noxa. JNK inhibition enhanced Mcl1-Noxa interaction in the mitochondrial fraction of infected cells, whereas overexpression of nonphosphorylatable Noxa resulted in enhanced mitochondria-mediated apoptosis in the infected epithelium. Because phosphorylation-dephosphorylation can regulate the apoptotic function of Noxa, this could be a potential target molecule for future treatment approaches for H. pylori-induced gastric cancer.
authors.affiliation: *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Suvasmita
authors.initials: S
authors.lastname: Rath
authors.affiliation: *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Lopamudra
authors.initials: L
authors.lastname: Das
authors.affiliation: *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Shrikant Babanrao
authors.initials: SB
authors.lastname: Kokate
authors.affiliation: *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Pratheek
authors.affiliation: *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Subhasis
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Chandan
authors.initials: C
authors.lastname: Goswami
authors.affiliation: *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Ranajoy
authors.initials: R
authors.lastname: Chattopadhyay
authors.affiliation: *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Sheila Eileen
authors.initials: SE
authors.lastname: Crowe
authors.affiliation: *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA asima@niser.ac.in.
authors.forename: Asima
authors.initials: A
authors.lastname: Bhattacharyya
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000821:virology; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D005434:Flow Cytometry; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D016480:Helicobacter pylori / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D048670:MAP Kinase Kinase 4; D008928:Mitochondria; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013270:Stomach / Q000473:pathology* / Q000821:virology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D048670:MAP Kinase Kinase 4
keywords: JNK; cytochrome c; gastric cancer; mitochondrial fragmentation; myeloid cell leukemia 1