title: Helicobacter pyloriInduced Phosphatidylinositol-3-OH Kinase/mTOR Activation Increases Hypoxia Inducible Factor-1α to Promote Loss of Cyclin D1 and G0/G1 Cell Cycle Arrest in Human Gastric Cells.
abstract: Helicobacter pylori(H. pylori) is a human gastric pathogen that has been linked to the development of several gastric pathologies, such as gastritis, peptic ulcer, and gastric cancer. In the gastric epithelium, the bacterium modifies many signaling pathways, resulting in contradictory responses that favor both proliferation and apoptosis. Consistent with such observations,H. pyloriactivates routes associated with cell cycle progression and cell cycle arrest.H. pyloriinfection also induces the hypoxia-induced factor HIF-1α, a transcription factor known to promote expression of genes that permit metabolic adaptation to the hypoxic environment in tumors and angiogenesis. Recently, however, also roles for HIF-1α in the repair of damaged DNA and inhibition of gene expression were described. Here, we investigated signaling pathways induced byH. pyloriin gastric cells that favor HIF-1α expression and the consequences thereof in infected cells. Our results revealed thatH. pyloripromoted PI3K/mTOR-dependent HIF-1α induction, HIF-1α translocation to the nucleus, and activity as a transcription factor as evidenced using a reporter assay. Surprisingly, however, transcription of known HIF-1α effector genes evaluated by qPCR analysis, revealed either no change (LDHA and GAPDH), statistically insignificant increases SLC2A1 (GLUT-1) or greatly enhance transcription (VEGFA), but in an HIF-1α-independent manner, as quantified by PCR analysis in cells with shRNA-mediated silencing of HIF-1α. Instead, HIF-1α knockdown facilitated G1/S progression and increased Cyclin D1 protein half-life, via a post-translational pathway. Taken together, these findings linkH. pylori-induced PI3K-mTOR activation to HIF-1α induced G0/G1 cell cycle arrest by a Cyclin D1-dependent mechanism. Thus, HIF-1α is identified here as a mediator between survival and cell cycle arrest signaling activated byH. pyloriinfection.
authors.affiliation: Laboratorio de Comunicaciones Celulares, Facultad De Medicina, Centro de Estudios Moleculares De la Célula, Centro de Estudios Avanzados en Enfermedades Crónicas, Programa De Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Jimena
authors.initials: J
authors.lastname: Canales
authors.affiliation: Laboratorio de Comunicaciones Celulares, Facultad De Medicina, Centro de Estudios Moleculares De la Célula, Centro de Estudios Avanzados en Enfermedades Crónicas, Programa De Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Universidad de ChileSantiago, Chile; Facultad de Ciencias de la Salud, Universidad Central de ChileSantiago, Chile.
authors.forename: Manuel
authors.initials: M
authors.lastname: Valenzuela
authors.affiliation: Laboratorio de Comunicaciones Celulares, Facultad De Medicina, Centro de Estudios Moleculares De la Célula, Centro de Estudios Avanzados en Enfermedades Crónicas, Programa De Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Jimena
authors.initials: J
authors.lastname: Bravo
authors.affiliation: Laboratorio de Comunicaciones Celulares, Facultad De Medicina, Centro de Estudios Moleculares De la Célula, Centro de Estudios Avanzados en Enfermedades Crónicas, Programa De Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Paulina
authors.initials: P
authors.lastname: Cerda-Opazo
authors.affiliation: Laboratorio de Comunicaciones Celulares, Facultad De Medicina, Centro de Estudios Moleculares De la Célula, Centro de Estudios Avanzados en Enfermedades Crónicas, Programa De Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Carla
authors.initials: C
authors.lastname: Jorquera
authors.affiliation: Laboratorio de Microbiología Molecular, Facultad de Medicina, Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Héctor
authors.initials: H
authors.lastname: Toledo
authors.affiliation: Laboratorio de Microbiología Oral, Departamento de Patología y Medicina Oral, Facultad De Odontología, Universidad de Chile Santiago, Chile.
authors.forename: Denisse
authors.initials: D
authors.lastname: Bravo
authors.affiliation: Laboratorio de Comunicaciones Celulares, Facultad De Medicina, Centro de Estudios Moleculares De la Célula, Centro de Estudios Avanzados en Enfermedades Crónicas, Programa De Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Andrew F G
authors.initials: AF
authors.lastname: Quest
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism* / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D051272:Glucose Transporter Type 1 / Q000187:drug effects / Q000378:metabolism; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D019938:Cyclin D1; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C530104:CCND1 protein, human; C497442:HIF1A protein, human; C495677:SLC2A1 protein, human; C467484:VEGFA protein, human; C546842:MTOR protein, human
keywords: Cyclin D1; HIF-1α; Helicobacter pylori; PI3K/mTOR; cell cycle arrest