Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)–ATF composite site to regulate Gadd153 expression during the stress response

Abstract

Gadd153, also known as chop, encodes a member of the CCAAT/enhancer-binding protein (C/EBP) transcription factor family and is transcriptionally activated by cellular stress signals. We recently demonstrated that arsenite treatment of rat pheochromocytoma PC12 cells results in the biphasic induction of Gadd153 mRNA expression, controlled in part through binding of C/EBPβ and two uncharacterized protein complexes to the C/EBP–ATF (activating transcription factor) composite site in the Gadd153 promoter. In this report, we identified components of these additional complexes as two ATF/CREB (cAMP-responsive-element-binding protein) transcription factors having differential binding activities dependent upon the time of arsenite exposure. During arsenite treatment of PC12 cells, we observed enhanced binding of ATF4 to the C/EBP–ATF site at 2 h as Gadd153 mRNA levels increased, and enhanced binding of ATF3 complexes at 6 h as Gadd153 expression declined. We further demonstrated that ATF4 activates, while ATF3 represses, Gadd153 promoter activity through the C/EBP–ATF site. ATF3 also repressed ATF4-mediated transactivation and arsenite-induced activation of the Gadd153 promoter. Our results suggest that numerous members of the ATF/CREB family are involved in the cellular stress response, and that regulation of stress-induced biphasic Gadd153 expression in PC12 cells involves the ordered, sequential binding of multiple transcription factor complexes to the C/EBP–ATF composite site.

Proteasome inhibitor induced gene expression profiles reveal overexpression of transcriptional regulators ATF3, GADD153 and MAD1

“…Two hours after addition of MG132, a speci®c and signi®cant increase in ATF3 and Gadd153 gene expression at the mRNA level was measured by real-time RT ± PCR (Table 2) con®rming an early and rapid stress response by transcriptional regulators. Both, Gadd153, also known as CHOP-10 or Ddit3, and the activating transcription factor ATF3 are transcription factors of the CCAAT/enhancer binding protein (C/EBP) family (Fawcett et al, 1999). Gadd153 is a small nuclear protein that dimerizes avidly with other members of the C/EBP family.…”

Roles of CHOP/GADD153 in endoplasmic reticulum stress

“…44 During arsenite-induced stress, ATF3 represses, while ATF4 activates, the expression of CHOP through time-dependent changes in the binding to the AARE. [47][48][49] ATF2 and ATF3 were reported Figure 3 Mechanism of transcriptional induction of CHOP in ER stress. Under ER stress conditions, BiP binds to unfolded proteins and thereby renders each ER stress transducers including PERK, ATF6 and Ire1 to be activated.…”

Cellular response to endoplasmic reticulum stress: a matter of life or death

“…102 Paradoxically, however, some components of the ESR are induced at the translational level when eIF2a is phosphorylated, including the transcription factor ATF4 and its downstream target CHOP, comprising a translationactivated response that promotes cell survival during ER and other stresses. 93,103 Although ATF4 mRNA is constitutively expressed, it is normally associated with monoribosomes and low molecular weight polyribosomes, indicating that it is inefficiently translated under resting conditions. 93,103 However, ATF4 mRNA quickly shifts to heavier ribosomal fractions and is selectively translated in a PERK-dependent fashion upon ER stress induction.…”