Role for activating transcription factor 3 in stress-induced beta-cell apoptosis.
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.
Hartman
Matthew G
MG
Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, Ohio State University, Columbus, USA.
Lu
Dan
D
Kim
Mi-Lyang
ML
Kociba
Gary J
GJ
Shukri
Tala
T
Buteau
Jean
J
Wang
Xiaozhong
X
Frankel
Wendy L
WL
Guttridge
Denis
D
Prentki
Marc
M
Grey
Shane T
ST
Ron
David
D
Hai
Tsonwin
T
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*
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D016207:Cytokines; D007328:Insulin; D014157:Transcription Factors; D005934:Glucagon