title: Hypoxia-induced deoxycytidine kinase expression contributes to apoptosis in chronic lung disease.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and tissue remodeling and is a leading cause of death in the United States. Increased apoptosis of pulmonary epithelial cells is thought to play a role in COPD development and progression. Identification of signaling pathways resulting in increased apoptosis in COPD can be used in the development of novel therapeutic interventions. Deoxyadenosine (dAdo) is a DNA breakdown product that amplifies lymphocyte apoptosis by being phosphorylated to deoxyadenosine triphosphate (dATP). dAdo is maintained at low levels by adenosine deaminase (ADA). This study demonstrated that mice lacking ADA developed COPD manifestations in association with elevated dAdo and dATP levels and increased apoptosis in the lung. Deoxycitidine kinase (DCK), a major enzyme for dAdo phosphorylation, was up-regulated in mouse and human airway epithelial cells in association with air-space enlargement. Hypoxia was identified as a novel regulator of DCK, and inhibition of DCK resulted in diminished dAdo-mediated apoptosis in the lungs. Our results suggest that activating the dAdo-DCK-dATP pathway directly results in increased apoptosis in the lungs of mice with air-space enlargement and suggests a novel therapeutic target for the treatment of COPD.
authors: Department of Biochemistry and Molecular Biology, University of Texas–Houston Medical School, Houston, TX 77030, USA.
authors: Tingting
authors: T
authors: Weng
authors: Harry
authors: H
authors: Karmouty-Quintana
authors: Luis J
authors: LJ
authors: Garcia-Morales
authors: Jose G
authors: JG
authors: Molina
authors: Mesias
authors: M
authors: Pedroza
authors: Raquel R
authors: RR
authors: Bunge
authors: Brian A
authors: BA
authors: Bruckner
authors: Matthias
authors: M
authors: Loebe
authors: Harish
authors: H
authors: Seethamraju
authors: Michael R
authors: MR
authors: Blackburn
mesh_terms: D015762:2-Chloroadenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000172:deficiency; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D003838:Deoxyadenine Nucleotides / Q000378:metabolism*; D003839:Deoxyadenosines / Q000378:metabolism* / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051379:Mice; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D015854:Up-Regulation
chemical_list: D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D015762:2-Chloroadenosine; C036854:2'-chloro-2'-deoxyadenosine; D003842:Deoxycytidine Kinase; D000243:Adenosine Deaminase; C026600:2'-deoxyadenosine triphosphate
references: Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):816-20
references: 18600545
references: Anticancer Drugs. 2010 Jul;21(6):591-9
references: 20436341
references: J Biol Chem. 1983 Oct 25;258(20):12334-40
references: 6605343
references: Health Technol Assess. 2009 Sep;13 Suppl 2:1-7
references: 19804683
references: Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1335-42
references: 15571254
references: Biochem Pharmacol. 2002 Sep;64(5-6):993-8
references: 12213597
references: Eur J Cancer. 1995;31A(2):202-8
references: 7718326
references: J Immunol. 2011 Apr 1;186(7):4367-74
references: 21357264
references: Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5551-6
references: 20080663
references: Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3673-7
references: 7731963
references: N Engl J Med. 2011 Feb 17;364(7):656-65
references: 21323543
references: J Intern Med. 2005 Dec;258(6):479-517
references: 16313474
references: PLoS One. 2010 Feb 16;5(2):e9224
references: 20169073
references: Trends Pharmacol Sci. 2003 Feb;24(2):66-70
references: 12559769
references: Immunol Cell Biol. 2010 Feb;88(2):165-71
references: 19841638
references: Biochem Pharmacol. 2003 Jun 15;65(12):2031-9
references: 12787883
references: Biochem Pharmacol. 2003 Feb 15;65(4):573-80
references: 12566084
references: Breast Cancer Res Treat. 2012 Feb;131(3):809-18
references: 21465168
references: Clin Cancer Res. 2006 Apr 15;12(8):2492-7
references: 16638857
references: FASEB J. 2006 Nov;20(13):2242-50
references: 17077301
references: Curr Opin Cell Biol. 2001 Apr;13(2):167-71
references: 11248550
references: Acta Biochim Biophys Sin (Shanghai). 2010 Jul;42(7):483-8
references: 20705587
references: J Clin Invest. 2002 Oct;110(7):993-1002
references: 12370277
references: Antioxid Redox Signal. 2011 Oct 15;15(8):2221-34
references: 21126189
references: J Biol Chem. 2003 Dec 12;278(50):49901-10
references: 14514691
references: Adv Exp Med Biol. 1998;431:641-5
references: 9598144
references: Prog Nucleic Acid Res Mol Biol. 1996;55:195-226
references: 8787611
references: Int J Mol Med. 2000 Mar;5(3):253-9
references: 10677565
references: J Exp Med. 2004 Dec 6;200(11):1395-405
references: 15583013
references: Respir Res. 2006 Mar 30;7:53
references: 16571143
references: Drugs Aging. 2005;22(12):983-1012
references: 16363884
references: Biochem Biophys Res Commun. 1999 Dec 29;266(3):699-717
references: 10603308
references: Adv Immunol. 2005;86:1-41
references: 15705418
references: Blood. 2009 Jan 1;113(1):224-32
references: 18812468
references: Am J Respir Cell Mol Biol. 1996 Apr;14(4):309-15
references: 8600933
references: J Clin Invest. 2000 Dec;106(11):1311-9
references: 11104784
references: Pharmacol Ther. 2009 Jul;123(1):105-16
references: 19426761
references: Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012 May;28(3):234-8
references: 22860423
references: Curr Opin Anaesthesiol. 2011 Aug;24(4):363-9
references: 21659868
references: J Biol Chem. 2000 Oct 13;275(41):32114-21
references: 10908569
references: J Exp Med. 2005 Dec 5;202(11):1493-505
references: 16330813
references: Microvasc Res. 2006 Jul-Sep;72(1-2):48-53
references: 16828810
references: Expert Rev Anticancer Ther. 2008 Apr;8(4):511-23
references: 18402518
references: J Immunol. 2008 Dec 1;181(11):8153-61
references: 19018008
references: Bull Cancer. 2007;94 Spec No Actualites:S127-33
references: 17845982
references: Nat Rev Mol Cell Biol. 2007 May;8(5):405-13
references: 17377525