title: Role for activating transcription factor 3 in stress-induced beta-cell apoptosis.
abstract: Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced beta-cell apoptosis. First, ATF3 is induced in beta cells by signals relevant to beta-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-kappaB and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in beta cells develop abnormal islets and defects secondary to beta-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine- or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced beta-cell apoptosis.
authors.affiliation: Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, Ohio State University, Columbus, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Hartman
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Mi-Lyang
authors.initials: ML
authors.lastname: Kim
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Kociba
authors.forename: Tala
authors.initials: T
authors.lastname: Shukri
authors.forename: Jean
authors.initials: J
authors.lastname: Buteau
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Wang
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Frankel
authors.forename: Denis
authors.initials: D
authors.lastname: Guttridge
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Tsonwin
authors.initials: T
authors.lastname: Hai
mesh_terms: D051700:Activating Transcription Factor 3; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000032:analysis; D007328:Insulin / Q000032:analysis; D007515:Islets of Langerhans / Q000737:chemistry / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000737:chemistry / Q000473:pathology; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D016207:Cytokines; D007328:Insulin; D014157:Transcription Factors; D005934:Glucagon