title: Mechanism of copper-activated transcription: activation of AP-1, and the JNK/SAPK and p38 signal transduction pathways.
abstract: Copper is an essential metal that is able to produce reactive oxygen species and to induce intracellular oxidative stress. Several studies have examined the effects of excessive copper and oxidative stress on various organisms and tissues, but few have addressed the molecular mechanisms by which copper affects transcription. Our results demonstrated that, in COS-7 cells, copper treatment caused an increase in the binding of nuclear proteins to activating protein-1 and antioxidant response elements. The level of copper-inducible nuclear protein binding was modulated by increasing or decreasing the level of intracellular oxidative stress. Copper exposure also led to an increase in the steady-state levels of c-fos, c-jun, and c-myc mRNAs. Exposure to copper resulted in an increase in the levels of phosphorylation and activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 pathways. The activation of these pathways resulted in a concomitant increase in c-Jun phosphorylation. We investigated the hypothesis that copper-induced oxidative stress leads to the formation of stable lipid peroxidation by-products that activate mitogen-activated protein kinase (MAPK) pathways, ultimately affecting transcription. While exposure did result in the production of 4-hydroxynonenal, the timing of the increased levels of proto-oncogene mRNA, phosphorylation of c-jun, and phosphorylation and activation of MAPKs, as well as the inability of the lipophilic antioxidant vitamin E to abrogate MAPK phosphorylation, suggest that the formation of stable lipid peroxidation by-products may not be the primary mechanism by which copper activates MAPKs. These results further elucidate the effects of copper on signal transduction pathways to alter gene expression.
authors.affiliation: Nicholas School of the Environment and Earth Sciences, Duke University, Durham, NC 27708, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Mattie
authors.forename: Matthew K
authors.initials: MK
authors.lastname: McElwee
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Freedman
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003300:Copper / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014810:Vitamin E; D003300:Copper; D008668:Metallothionein; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal
references.citation: Biochem Mol Biol Int. 1996 Aug;39(6):1201-7
references.pmid: 8876974
references.citation: Arch Dis Child. 1982 Dec;57(12):922-8
references.pmid: 7181521
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Nucleic Acids Res. 1994 Nov 25;22(23):5016-23
references.pmid: 7800494
references.citation: Immunobiology. 1995 Jul;193(2-4):143-8
references.pmid: 8530137
references.citation: Chem Biol Interact. 2006 Mar 10;160(1):1-40
references.pmid: 16430879
references.citation: Environ Toxicol Chem. 2003 Nov;22(11):2768-74
references.pmid: 14587920
references.citation: Hepatology. 1999 May;29(5):1565-72
references.pmid: 10216144
references.citation: Cancer Res. 2003 Sep 15;63(18):5940-9
references.pmid: 14522920
references.citation: Ecotoxicol Environ Saf. 1990 Dec;20(3):307-24
references.pmid: 2090445
references.citation: FASEB J. 1997 Sep;11(11):851-7
references.pmid: 9285483
references.citation: Trends Neurosci. 1997 May;20(5):227-31
references.pmid: 9141200
references.citation: Biometals. 2003 Mar;16(1):103-11
references.pmid: 12572670
references.citation: Crit Rev Oncog. 1995;6(2):99-115
references.pmid: 8792086
references.citation: J Neurochem. 2000 Jan;74(1):159-68
references.pmid: 10617117
references.citation: J Environ Pathol Toxicol Oncol. 2000;19(3):297-305
references.pmid: 10983896
references.citation: Adv Pharmacol. 1996;36:121-37
references.pmid: 8783557
references.citation: Curr Opin Cell Biol. 1995 Dec;7(6):798-805
references.pmid: 8608010
references.citation: J Clin Invest. 1998 Dec 1;102(11):1942-50
references.pmid: 9835619
references.citation: J Biol Chem. 1999 Jan 22;274(4):2234-42
references.pmid: 9890986
references.citation: Cancer Surv. 1996;27:101-25
references.pmid: 8909797
references.citation: Ecotoxicol Environ Saf. 1998 May-Jun;40(1-2):49-55
references.pmid: 9626535
references.citation: J Dermatol Sci. 1996 Sep;12(3):255-62
references.pmid: 8884531
references.citation: Pediatr Int. 2000 Jun;42(3):289-92
references.pmid: 10881588
references.citation: Ecotoxicol Environ Saf. 1997 Mar;36(2):183-8
references.pmid: 9126437
references.citation: Arch Environ Contam Toxicol. 2004 Jan;46(1):61-6
references.pmid: 15025165
references.citation: Mol Cell Biochem. 2001 Jun;222(1-2):85-95
references.pmid: 11678615
references.citation: Antioxid Redox Signal. 2005 Jan-Feb;7(1-2):42-59
references.pmid: 15650395
references.citation: Brain Res Brain Res Rev. 1998 Dec;28(3):370-490
references.pmid: 9858769
references.citation: Toxicol Sci. 2001 Jun;61(2):283-94
references.pmid: 11353137
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12908-13
references.pmid: 8917518
references.citation: Crit Rev Biochem Mol Biol. 1993;28(3):173-207
references.pmid: 8325038
references.citation: Toxicol Sci. 2001 Jun;61(2):295-303
references.pmid: 11353138
references.citation: Am J Physiol. 1998 Sep;275(3):L551-8
references.pmid: 9728050
references.citation: Arch Environ Contam Toxicol. 2003 Oct;45(3):357-63
references.pmid: 14674589
references.citation: Carcinogenesis. 1999 Apr;20(4):663-8
references.pmid: 10223197
references.citation: Curr Opin Immunol. 1996 Jun;8(3):402-11
references.pmid: 8793994
references.citation: J Environ Pathol Toxicol Oncol. 2000;19(3):179-99
references.pmid: 10983886
references.citation: Science. 1995 Nov 24;270(5240):1326-31
references.pmid: 7481820
references.citation: Am J Respir Cell Mol Biol. 1995 Oct;13(4):387-98
references.pmid: 7546768
references.citation: Bull Environ Contam Toxicol. 1978 May;19(5):608-16
references.pmid: 667389
references.citation: J Cell Biochem. 2002;87(1):29-38
references.pmid: 12210719
references.citation: Free Radic Biol Med. 2000 May 1;28(9):1370-8
references.pmid: 10924856
references.citation: Anticancer Res. 2001 Jan-Feb;21(1A):261-7
references.pmid: 11299744
references.citation: Toxicol Sci. 2001 Jun;61(2):314-20
references.pmid: 11353140
references.citation: Bioessays. 1996 Jul;18(7):567-77
references.pmid: 8757935
references.citation: Comp Biochem Physiol C Comp Pharmacol Toxicol. 1987;86(1):169-71
references.pmid: 2881713
references.citation: Biochem Pharmacol. 1994 Aug 3;48(3):439-44
references.pmid: 8068030
references.citation: Ann N Y Acad Sci. 1993 May 28;686:262-78; discussion 278-9
references.pmid: 8512252
references.citation: Biochem Biophys Res Commun. 1993 Aug 16;194(3):1044-50
references.pmid: 8352762
references.citation: Biochem Biophys Res Commun. 2001 Jul 27;285(4):921-5
references.pmid: 11467839
references.citation: Ecotoxicol Environ Saf. 1998 Jan;39(1):41-7
references.pmid: 9515074
references.citation: Mol Carcinog. 1999 Jul;25(3):219-29
references.pmid: 10411148
references.citation: Cancer Res. 1992 Sep 15;52(18):4866-71
references.pmid: 1516044
references.citation: Toxicol Lett. 2002 Jul 7;133(1):33-45
references.pmid: 12076508
references.citation: Am J Physiol Cell Physiol. 2004 Feb;286(2):C293-301
references.pmid: 14576086
references.citation: Comp Biochem Physiol C Comp Pharmacol Toxicol. 1988;90(1):69-72
references.pmid: 2904875
references.citation: Ecotoxicol Environ Saf. 1992 Jun;23(3):282-93
references.pmid: 1376233
references.citation: EMBO J. 1996 Apr 15;15(8):1914-23
references.pmid: 8617238
references.citation: Environ Toxicol Chem. 2003 Apr;22(4):845-54
references.pmid: 12685721
references.citation: Am J Physiol. 1998 Nov;275(5):L861-9
references.pmid: 9815102