Analysis of ATF3, a Transcription Factor Induced by Physiological Stresses and Modulated by gadd153/Chop10

Abstract

We demonstrate that ATF3, a member of the ATF/CREB family of transcription factors, is induced in a variety of stressed tissues: mechanically injured liver, toxin-injured liver, blood-deprived heart, and postseizure brain. We also demonstrate that an ATF3-interacting protein, gadd153/Chop10, forms a nonfunctional heterodimer with ATF3: the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. Interestingly, ATF3 and gadd153/ Chop10 are expressed in inverse but overlapping manners during the liver's response to carbon tetrachloride (CCl 4 ): the level of gadd153/Chop10 mRNA is high in the normal liver and greatly decreases upon CCl 4 treatment; the level of ATF3 mRNA, on the other hand, is low in the normal liver and greatly increases upon CCl 4 treatment. We hypothesize that in nonstressed liver, gadd153/Chop10 inhibits the limited amount of ATF3 by forming an inactive heterodimer with it, whereas in CCl 4 -injured liver, the synthesis of gadd153/ Chop10 is repressed, allowing the induced ATF3 to function.

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

“…In particular, GATA-3 and CA150 were repressed, whereas the C/EBP family members Gadd153 and ATF3 were strongly induced. The two proteins Gadd153 and ATF3 heterodimerize to regulate the expression of a large number of cAMP response genes in either a positive or negative manner (Chen et al, 1996a;Fawcett et al, 1996). In this study, the induction and/or stabilization of both was con®rmed at the mRNA level by real-time reverse transcriptase PCR (Table 2) and at the protein level by Western blotting (Figure 2).…”

“…The stress-inducible transcription factor ATF3 is interacting with and modulated by Gadd153 (Chen et al, 1996a), forming a heterodimer that, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. Inversely, ATF3 function is inhibited by Gadd153 (Wolfgang et al, 1997).…”

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

“…Overexpression of CHOP in the bone microenvironment in vivo also may result in important interactions with Fos and Jun or with ATF-4, a member of the ATF/CREB family, and explain the osteopenia observed in CHOP transgenics [11,12]. ATF-4 has important effects on osteoblast function and atf4 null mice exhibit decreased osteoblastic activity, whereas forced ATF-4 expression induces osteoblastic gene markers [22,46].…”

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.…”

“…NF-Y constitutively binds to the CCAAR part of ERSE1 and ERSE2 to be induced under hypoxia, which induces ER stress. 47,50 Therefore, they may also regulate the expression of CHOP in ER stress.…”