Role for activating transcription factor 3 in stress-induced β-cell apoptosis

Matthew G. Hartman, Dan Lu, Mi Lyang Kim, Gary J. Kociba, Tala Shukri, Jean Buteau, Xiaozhong Wang, Wendy L. Frankel, Denis Guttridge, Marc Prentki, Shane T. Grey, David Ron, Tsonwin Hai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

238 Scopus citations

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 β-cell apoptosis. First, ATF3 is induced in β cells by signals relevant to β-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-κB 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 β cells develop abnormal islets and defects secondary to β-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 β-cell apoptosis.

Original languageEnglish (US)
Pages (from-to)5721-5732
Number of pages12
JournalMolecular and cellular biology
Volume24
Issue number13
DOIs
StatePublished - Jul 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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