title: The unfolded protein response in melanocytes: activation in response to chemical stressors of the endoplasmic reticulum and tyrosinase misfolding.
abstract: Accumulation of proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), comprising three signaling pathways initiated by Ire1, Perk and Atf6 respectively. Unfolded protein response activation was compared in chemically stressed murine wildtype melanocytes and mutant melanocytes that retain tyrosinase in the ER. Thapsigargin, an ER stressor, activated all pathways in wildtype melanocytes, triggering Caspase 12-mediated apoptosis at toxic doses. Albino melanocytes expressing mutant tyrosinase showed evidence of ER stress with increased Ire1 expression, but the downstream effector, Xbp1, was not activated even following thapsigargin treatment. Attenuation of Ire1 signaling was recapitulated in wildtype melanocytes treated with thapsigargin for 8 days, with diminished Xbp1 activation observed after 4 days. Atf6 was also activated in albino melanocytes, with no response to thapsigargin, while the Perk pathway was not activated and thapsigargin treatment elicited robust expression of the downstream effector CCAAT-enhancer-binding protein homologous protein. Thus, melanocytes adapt to ER stress by attenuating two UPR pathways.
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA. prashiela.manga@nyumc.org
authors.forename: Prashiela
authors.initials: P
authors.lastname: Manga
authors.forename: Sabina
authors.initials: S
authors.lastname: Bis
authors.forename: Kristen
authors.initials: K
authors.lastname: Knoll
authors.forename: Beremis
authors.initials: B
authors.lastname: Perez
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Orlow
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D014442:Monophenol Monooxygenase / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D053454:Caspase 12; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D014442:Monophenol Monooxygenase; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000071701:Regulatory Factor X Transcription Factors; D019284:Thapsigargin; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C497112:Atf6 protein, mouse; C000605544:Xbp1 protein, mouse; C052617:Bcl2 protein, mouse; C486556:Ern2 protein, mouse
references.citation: Semin Cell Dev Biol. 2007 Dec;18(6):716-31
references.pmid: 18023214
references.citation: Mol Cell. 2007 Jul 6;27(1):53-66
references.pmid: 17612490
references.citation: FASEB J. 2001 Oct;15(12):2149-61
references.pmid: 11641241
references.citation: J Cell Physiol. 2010 Mar;222(3):502-8
references.pmid: 20020442
references.citation: Pigment Cell Melanoma Res. 2008 Jun;21(3):358-67
references.pmid: 18476909
references.citation: J Clin Invest. 2008 Oct;118(10):3378-89
references.pmid: 18776938
references.citation: J Biol Chem. 2001 Feb 23;276(8):5924-31
references.pmid: 11069924
references.citation: Physiol Rev. 2006 Oct;86(4):1133-49
references.pmid: 17015486
references.citation: Carcinogenesis. 2007 Nov;28(11):2328-36
references.pmid: 17652336
references.citation: Biochem J. 2001 Apr 15;355(Pt 2):259-69
references.pmid: 11284711
references.citation: Neuron. 2008 Feb 7;57(3):393-405
references.pmid: 18255032
references.citation: J Biol Chem. 1998 Dec 11;273(50):33741-9
references.pmid: 9837962
references.citation: Cancer Res. 2005 May 15;65(10):4292-9
references.pmid: 15899821
references.citation: J Biol Chem. 2004 May 7;279(19):20108-17
references.pmid: 14978030
references.citation: FASEB J. 2007 Dec;21(14):4013-27
references.pmid: 17660348
references.citation: EMBO J. 2004 Mar 10;23(5):1207-16
references.pmid: 15010700
references.citation: J Biol Chem. 2006 Oct 20;281(42):31440-7
references.pmid: 16928686
references.citation: Cancer Res. 2007 Jun 15;67(12):5880-8
references.pmid: 17575157
references.citation: Mol Cell Biol. 2000 Sep;20(18):6755-67
references.pmid: 10958673
references.citation: Pigment Cell Melanoma Res. 2009 Jun;22(3):307-18
references.pmid: 19192212
references.citation: Science. 2007 Nov 9;318(5852):944-9
references.pmid: 17991856
references.citation: Mol Cancer Res. 2008 Aug;6(8):1308-15
references.pmid: 18667591
references.citation: Endocrinology. 2009 Jul;150(7):3197-206
references.pmid: 19282378
references.citation: Neoplasia. 2009 May;11(5):436-47
references.pmid: 19412428
references.citation: J Invest Dermatol. 2004 Nov;123(5):930-6
references.pmid: 15482482
references.citation: Cancer Res. 1998 Apr 15;58(8):1609-15
references.pmid: 9563469
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5889-94
references.pmid: 10823941
references.citation: PLoS Genet. 2009 Jun;5(6):e1000523
references.pmid: 19543371
references.citation: Mol Cell Biol. 2003 Nov;23(21):7448-59
references.pmid: 14559994
references.citation: Glycoconj J. 2009 Aug;26(6):691-5
references.pmid: 19015978
references.citation: Mol Cell. 2003 Mar;11(3):619-33
references.pmid: 12667446
references.citation: Mol Biol Cell. 2002 Jun;13(6):1953-64
references.pmid: 12058062
references.citation: Mol Biol Cell. 2005 Aug;16(8):3740-52
references.pmid: 15958486
references.citation: J Cell Sci. 2003 Aug 1;116(Pt 15):3203-12
references.pmid: 12829739
references.citation: Nat Cell Biol. 2000 Jun;2(6):326-32
references.pmid: 10854322
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):153-8
references.pmid: 14660795
references.citation: Dev Cell. 2002 Jul;3(1):99-111
references.pmid: 12110171
references.citation: Biochem J. 1999 Apr 1;339 ( Pt 1):135-41
references.pmid: 10085237
references.citation: Br J Cancer. 2009 Nov 17;101(10):1692-8
references.pmid: 19861963
references.citation: J Biol Chem. 2003 Jul 11;278(28):25607-17
references.pmid: 12724309
references.citation: Nature. 2002 Jan 3;415(6867):92-6
references.pmid: 11780124
references.citation: PLoS One. 2009;4(1):e4170
references.pmid: 19137072
references.citation: Nat Rev Immunol. 2008 Sep;8(9):663-74
references.pmid: 18670423
references.citation: Development. 1989 Feb;105(2):379-85
references.pmid: 2806130
references.citation: Mol Cell. 2000 May;5(5):897-904
references.pmid: 10882126