title: Spontaneously hyperactive MEK-Erk pathway mediates paradoxical facilitation of cell proliferation in mild hypoxia.
abstract: BACKGROUND
  Oxygen is important for common eukaryotic cells to generate ATP. Pathophysiological conditions such as ischemic diseases cause tissue hypoxia. In addition, oxygen availability in deep tissues is supposed to be far lower than surrounding atmosphere even in healthy animals, and the oxygen partial pressures in most normal tissues are estimated to be around 40-50mmHg, so-called mild hypoxia. Recent studies have demonstrated that mild hypoxia has distinct effects on living cells from severe hypoxia. For instance, mild hypoxia was reported to promote cell reprogramming. Although severe hypoxia is known to inhibit cell proliferation, mild hypoxia has been paradoxically demonstrated to increase cell proliferation. However, it has not been clarified by which molecular mechanisms mild hypoxia evokes the discontinuous increment of cell proliferation.
  
  
  METHODS
  We established experimental conditions showing the opposite influences of mild and severe hypoxia on cell proliferation using undifferentiated Caco2 human colon carcinoma cells in order to clarify the underlying molecular mechanism.
  
  
  RESULTS
  The basal activity of Erk, which is a typical mediator of mitogenic signals, is spontaneously increased specifically in cells exposed to mild hypoxia, and inhibition of MEK, an upstream kinase of the Erk, completely inhibited the mild hypoxia-induced enhancement of cell proliferation.
  
  
  CONCLUSIONS
  Spontaneous hyperactivation of the MEK-Erk pathway by mild hypoxia should be the plausible molecular mechanism of the paradoxical promotion of cell proliferation.
  
  
  CONCLUSIONS
  Our findings will provide clues to the molecular basis of mild hypoxia-evoked phenomena such as cell reprogramming.
authors.affiliation: Laboratory of Pharmacology and Physiological Sciences, Frontier Laboratory for Pharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan; Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan. Electronic address: licht.ph@gmail.com.
authors.forename: Licht
authors.initials: L
authors.lastname: Miyamoto
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan; Department of Clinical Pharmacy, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yagi
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Hatano
authors.affiliation: Department of Clinical Pharmacy, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kawazoe
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: Department of Clinical Pharmacy, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Minakuchi
authors.affiliation: Division of Molecular Pharmacology, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan. Electronic address: tsuchiya@tokushima-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
mesh_terms: D018938:Caco-2 Cells; D015687:Cell Hypoxia; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D010766:Phosphorylation
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Caco2 cells; Cell proliferation; Cell reprogramming; Erk; MAP kinase cascade; Mild hypoxia