Transcription factor ATF2 regulates gene expression in response to environmental changes. Upon exposure to cellular stresses, the mitogen-activated proteinkinase (MAPK) cascades including SAPK/JNK and p38 can enhance ATF2's transactivating function through phosphorylation of Thr69 and Thr71. However, the mechanism of ATF2 activation by growth factors that are poor activators of JNK and p38 is still elusive. Here, we show that in ®broblasts, insulin, epidermal growth factor (EGF) and serum activate ATF2 via a so far unknown two-step mechanism involving two distinct Ras effector pathways: the Raf±MEK±ERK pathway induces phosphorylation of ATF2 Thr71, whereas subsequent ATF2 Thr69 phosphorylation requires the Ral±RalGDS±Src±p38 pathway. Cooperation between ERK and p38 was found to be essential for ATF2 activation by these mitogens; the activity of p38 and JNK/SAPK in growth factorstimulated ®broblasts is insuf®cient to phosphorylate ATF2 Thr71 or Thr69 + 71 signi®cantly by themselves, while ERK cannot dual phosphorylate ATF2 Thr69 + 71 ef®ciently. These results reveal a so far unknown mechanism by which distinct MAPK pathways and Ras effector pathways cooperate to activate a transcription factor. Keywords: ATF2/ERK/mitogens/p38/Ras Introduction ATF2 is a ubiquitously expressed member of the basic region-leucine zipper (bZIP) transcription factor family that can regulate gene expression in response to changes in the cellular environment. ATF2 plays an important role in placenta formation and skeletal and central nervous system development (Reimold et al., 1996;Maekawa et al., 1999) and is involved in oncogenic transformation and in adaptive responses of the cell to viral infections and (geno)toxic stresses (Liu and Green, 1990;Reimold et al., 1996;Ronai et al., 1998;Maekawa et al., 1999;Falvo et al., 2000;van Dam and Castellazzi, 2001). ATF2 binds its target promoter/enhancers as a homodimer or as a heterodimer with a restricted group of other bZip proteins, the most well known of which is the c-jun oncogene product.Heterodimerization of ATF2 appears to be crucial for at least some of its functions; for instance, the oncogenic activity of ATF2 in chicken cells critically depends on its ability to dimerize with cJun . ATF2 is also assumed to play a role in cJun-dependent cell cycle progression, cell survival and apoptosis, in addition to the Fos family members (Johnson et al., 1993;Ham et al., 1995;Verheij et al., 1996;Bossy-Wetzel et al., 1997;Le Niculescu et al., 1999;Schreiber et al., 1999;Wisdom et al., 1999;Kolbus et al., 2000). cJun±ATF2 and ATF2±ATF2 complexes recognize sequence motifs (8 bp) different from the 7 bp motifs bound by cJun±Fos AP-1 complexes (Benbrook and Jones, 1990;Ivashkiv et al., 1990;Hai and Curran, 1991;Chatton et al., 1994), and on minimal promoters cJun±ATF2 heterodimers are more potent transcriptional activators than ATF2±ATF2 homodimers (Benbrook and Jones, 1990;Huguier et al., 1998;. cJun±ATF2 target genes implicated in growth control include c-jun itself, ATF3, cyclin D1 and cyclin A ...

South Asians (SAs) develop type 2 diabetes at a younger age and lower BMI compared with Caucasians (Cs). The underlying cause is still poorly understood but might result from an innate inability to adapt to the Westernized diet. This study aimed to compare the metabolic adaptation to a high-fat, high-calorie (HFHC) diet between both ethnicities. Twelve healthy, young lean male SAs and 12 matched Cs underwent a two-step hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies and indirect calorimetry before and after a 5-day HFHC diet. Hepatic triglyceride content (HTG) and abdominal fat distribution were assessed using magnetic resonance imaging and spectroscopy. At baseline, SAs had higher insulin clamp levels than Cs, indicating reduced insulin clearance rate. Despite the higher insulin levels, endogenous glucose production was comparable between groups, suggesting lower hepatic insulin sensitivity in SAs. Furthermore, a 5-day HFHC diet decreased the insulin-stimulated (nonoxidative) glucose disposal rate only in SA. In skeletal muscle, no significant differences were found between groups in insulin/mammalian target of rapamycin signaling, metabolic gene expression, and mitochondrial respiratory chain content. Furthermore, no differences in (mobilization of) HTG and abdominal fat were detected. We conclude that HFHC feeding rapidly induces insulin resistance only in SAs. Thus, distinct adaptation to Western food may partly explain their propensity to develop type 2 diabetes.

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