Role for Activating Transcription Factor 3 in Stress-Induced β-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 ␤-cell apoptosis. First, ATF3 is induced in ␤ cells by signals relevant to ␤-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-B 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 ␤ cells develop abnormal islets and defects secondary to ␤-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 ␤-cell apoptosis.It is widely accepted that autoimmunity is the main cause of type 1 but not type 2 diabetes. Despite this difference, ␤-cell death plays an important role in the pathophysiological progression of both diseases (15,43,45). On one hand, proinflammatory cytokines (interleukin-1␤ , tumor necrosis factor alpha [TNF-␣], and gamma interferon [IFN-␥]) destroy ␤ cells in the islets of Langerhans, leading to the pathogenesis of type 1 diabetes (11,14,15,42); on the other hand, elevated glucose and free fatty acids (FFAs)-common metabolic abnormalities in type 2 diabetes-induce ␤-cell death, contributing to the progression of the disease (13,32,35,53,62). Emerging evidence indicates that activation of the NF-B and Jun N-terminal kinase/stress-activated protein kinase (JNK/ SAPK) signaling pathways is a key event leading to cell death, when ␤ cells are exposed to these signals: proinflammatory cytokines, elevated glucose, and elevated FFAs (12,15,16,43,49). Furthermore, activation of these pathways has been demonstrated to impair insulin signaling (1,17,18,36) and play a role in type 2 diabetes (63,71). Therefore, these stress-activated signaling pathways constitute a common molecular mechanism in the pathophysiological progression of type 1 and type 2 diabetes.Thus far, inducible nitric oxide (NO) synthase (iNOS), whose expression leads to NO production, is one of the best known target genes for these pathways (14-16, 42, 54). Several lines of evidence indicate that iNOS plays an important role in the pathogenesis of diabetes. (i) iNOS is induced in the islets by cytokines (16) and is expressed in the islets of diabetes prone BB rats (33) and nonobese diabetic (NOD) mice (55,58). (ii) Transgenic mice expressing iNOS in ␤ cells develop ␤-cell destruction and diabetes (60). (iii) ␤ cells lacking functional iNOS are partially protected ...

Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes

“…Evidence of enhanced expression of activating transcription factor 3 in type 1 diabetic beta cells has been presented [8], whereas CHOP was not found [4]. Conversely, studies on pancreases from patients with type 2 diabetes revealed increased levels of CHOP, BIP and activating transcription factor ATF-3 [3,4,8] as well as ER dilation [9].…”

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…As an adaptive response to ER stress, pancreatic beta cells express high levels of the transducers inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK) and activating transcription factor-6 (ATF6), which balance the protein synthesis and ER folding capacity of the cells. Despite an increase in unfolded protein response (UPR) signalling, which allows proinsulin synthesis by increasing the ER folding capacity after acute exposure to hyperglycaemia [137], chronic ER stress leads to a decrease in insulin synthesis and activation of the apoptotic cell death programme [138]. NEFA have been recognised as key contributors that can trigger the apoptotic programme, in part mediated by the ER stress response, and this highlights the significance of obesity and nutrients in the context of lipotoxic effects on beta cells [139].…”

Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathway

“…ATF3 has been suggested to be critical in metastasis, and has also been reported to be proapoptotic as well as antiapoptotic (Ishiguro and Nagawa, 2000;Hai and Hartman, 2001;Francis et al, 2004;Hartman et al, 2004). As this paper was Anoxic induction of ATF3 K Ameri et al completed, it was reported that ATF3 stabilizes p53 upon genotoxic stress (Yan et al, 2005), and also induces tubulogenic differentiation in endothelial cells and angiogenesis in diabetic angiopathy (Okamoto et al, 2006).…”

“…Similarly, the JNK inhibitor SP600125 also reduced the levels of induction of ATF3 under anoxia and by DFO (Figure 4d). MKK7 can directly regulate JNK activity (Tournier et al, 1997), and this signalling pathway has been previously suggested to be involved in regulating the expression of ATF3 (Cai et al, 2000;Hartman et al, 2004;Inoue et al, 2004). We investigated the potential role of MKK7 in induction of ATF3 protein under anoxia.…”

“…Second, expression of ATF3 has been demonstrated to alter a variety of cellular processes relevant to cancer progression including cell cycle, cell death, angiogenesis and metastasis (Hai and Hartman, 2001;Okamoto et al, 2006). Third, ATF3 expression can be regulated transcriptionally by a variety of signalling pathways or transcription factors, including nuclear factor kappa B (Hartman et al, 2004), EGR-1 (Bottone et al, 2005), by p53-dependent and -independent pathways (Amundson et al, 1999;Fan et al, 2002), and by the c-Jun NH 2 -terminal kinase (JNK) (Cai et al, 2000), which is activated by MKK7 (Tournier et al, 1997). In addition to promoter activation, ATF3 mRNA can also accumulate as a result of mRNA stabilization (Liang et al, 1996).…”