title: Role of p38 and JNK MAPK signaling pathways and tumor suppressor p53 on induction of apoptosis in response to Ad-eIF5A1 in A549 lung cancer cells.
abstract: BACKGROUND
  The eukaryotic translation initiation factor 5A1 (eIF5A1) is a highly conserved protein involved in many cellular processes including cell division, translation, apoptosis, and inflammation. Induction of apoptosis is the only function of eIF5A1 that is known to be independent of post-translational hypusine modification. In the present study, we investigated the involvement of mitogen- and stress-activated protein kinases during apoptosis of A549 lung cancer cells infected with adenovirus expressing eIF5A1 or a mutant of eIF5A1 that cannot be hypusinated (eIF5A1K50A).
  
  
  METHODS
  Using adenoviral-mediated transfection of human A549 lung cancer cells to over-express eIF5A1 and eIF5A1K50A, the mechanism by which unhypusinated eIF5A1 induces apoptosis was investigated by Western blotting, flow cytometry, and use of MAPK and p53 inhibitors.
  
  
  RESULTS
  Phosphorylation of ERK, p38 MAPK, and JNK was observed in response to adenovirus-mediated over-expression of eIF5A1 or eIF5A1K50A, along with phosphorylation and stabilization of the p53 tumor suppressor protein. Synthetic inhibitors of p38 and JNK kinase activity, but not inhibitors of ERK1/2 or p53 activity, significantly inhibited apoptosis induced by Ad-eIF5A1. Importantly, normal lung cells were more resistant to apoptosis induced by eIF5A1 and eIF5A1K50A than A549 lung cancer cells.
  
  
  CONCLUSIONS
  Collectively these data indicate that p38 and JNK MAP kinase signaling are important for eIF5A1-induced cell death and that induction of apoptosis was not dependent on p53 activity.
authors: Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, ON N2L 3G1, Canada.
authors: Catherine A
authors: CA
authors: Taylor
authors: Qifa
authors: Q
authors: Zheng
authors: Zhongda
authors: Z
authors: Liu
authors: John E
authors: JE
authors: Thompson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D010448:Peptide Initiation Factors / Q000235:genetics*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D010448:Peptide Initiation Factors; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D048051:p38 Mitogen-Activated Protein Kinases; D000097574:Eukaryotic Translation Initiation Factor 5A
references: FEBS J. 2006 Mar;273(6):1102-14
references: 16519677
references: Oncogene. 2001 Mar 1;20(9):1076-84
references: 11314044
references: Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3568-76
references: 15452064
references: BMC Cell Biol. 2007 Feb 27;8:7
references: 17326836
references: Cancer Res. 2000 May 1;60(9):2464-72
references: 10811125
references: Curr Opin Cell Biol. 1998 Apr;10(2):205-19
references: 9561845
references: Oncogene. 1999 May 27;18(21):3205-12
references: 10359526
references: Genomics. 2001 Jan 1;71(1):101-9
references: 11161802
references: Apoptosis. 2007 Sep;12(9):1681-90
references: 17520191
references: J Infect Dis. 2008 Nov 1;198(9):1407-14
references: 18793104
references: Nature. 2012 Jul 12;487(7406):244-8
references: 22722845
references: Biochemistry. 1997 Aug 19;36(33):10117-24
references: 9254608
references: Nat Cell Biol. 2002 Nov;4(11):842-9
references: 12402042
references: Nat Genet. 1999 Mar;21(3):326-9
references: 10080190
references: Cancer Res. 2004 Jun 15;64(12):4197-200
references: 15205331
references: J Biol Chem. 2000 Nov 17;275(46):35778-85
references: 10958792
references: EMBO J. 1999 Dec 15;18(24):7002-10
references: 10601022
references: Biol Pharm Bull. 2010;33(10):1666-72
references: 20930373
references: Mol Ther. 2012 Jul;20(7):1305-14
references: 22588272
references: J Neurooncol. 2009 May;92(3):357-71
references: 19357962
references: Exp Cell Res. 2007 Feb 1;313(3):437-49
references: 17187778
references: Mol Cell Biol. 2006 Apr;26(7):2782-90
references: 16537920
references: Nature. 2009 May 7;459(7243):118-21
references: 19424157
references: J Biol Chem. 2004 Nov 19;279(47):49251-8
references: 15371445
references: Int J Biochem Cell Biol. 2007;39(12):2278-88
references: 17689131
references: Hum Pathol. 2008 Jan;39(1):80-6
references: 17949776
references: J Biol Chem. 2000 Jul 7;275(27):20444-9
references: 10781582
references: Biol Signals. 1997 May-Jun;6(3):166-74
references: 9285100
references: J Clin Invest. 2010 Jun;120(6):2156-70
references: 20501948
references: Mol Cell Biol. 2001 Oct;21(20):6913-26
references: 11564875
references: Cancer Biol Ther. 2004 Feb;3(2):156-61
references: 14764989
references: Mol Cell Biol. 2000 Feb;20(3):929-35
references: 10629050
references: Biofactors. 1993 May;4(2):95-104
references: 8347280
references: Oncogene. 1999 Jan 7;18(1):173-80
references: 9926932
references: J Biol Chem. 1997 Aug 29;272(35):22173-81
references: 9268362
references: EMBO J. 2003 Aug 1;22(15):3876-86
references: 12881422
references: Hepatology. 2010 Apr;51(4):1255-63
references: 20112425
references: J Biol Chem. 1997 Apr 11;272(15):10110-6
references: 9092556
references: Eur J Biochem. 2001 May;268(10):2764-72
references: 11358490
references: Nature. 2001 Mar 1;410(6824):37-40
references: 11242034
references: EMBO J. 2007 Jun 20;26(12):2856-67
references: 17525735
references: Cell. 1997 Oct 31;91(3):325-34
references: 9363941
references: Cell Death Differ. 2003 Apr;10(4):413-7
references: 12719718
references: Amino Acids. 2013 Jan;44(1):103-9
references: 22139412
references: Cell. 1995 Jan 27;80(2):293-9
references: 7834749
references: Nature. 1991 Oct 17;353(6345):670-4
references: 1922387
references: J Cell Physiol. 2010 Jun;223(3):798-809
references: 20232312
references: J Appl Toxicol. 2005 Sep-Oct;25(5):374-82
references: 16013042
references: J Biol Chem. 2004 Mar 5;279(10):8837-47
references: 14681225