Disease relevance of Ddit3

• 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/EBPbeta and two uncharacterized protein complexes to the C/EBP-ATF (activating transcription factor) composite site in the Gadd153 promoter [1].
• Gadd153 mRNA expression and GADD153 protein increased transiently at 2, 3, 5 and 7 days, and at 3 and 5 days after ischemia [2].

High impact information on Ddit3

• In all cell lines, overexpression of Gadd153 sensitized cells to ER stress [3].
• Investigation of the mechanisms contributing to this effect revealed that elevated Gadd153 expression results in the down-regulation of Bcl2 expression, depletion of cellular glutathione, and exaggerated production of reactive oxygen species [3].
• Restoration of Bcl2 expression in Gadd153-overexpressing cells led to replenishment of glutathione and a reduction in levels of reactive oxygen species, and it protected cells from ER stress-induced cell death [3].
• Several studies have correlated Gadd153 expression with cell death, but a mechanistic link between Gadd153 and apoptosis has never been demonstrated [3].
• This effect was absent in young cells and in old cells of CR rats. gadd153 induction by EGF was reactive oxygen species-dependent and correlated with heightened sensitivity to subsequent H(2)O(2) treatment, suggesting that elevated Gadd153 contributes to the greater sensitivity of EGF-pretreated old cells to oxidative stress [4].

Biological context of Ddit3

• We conclude that Gadd153 sensitizes cells to ER stress through mechanisms that involve down-regulation of Bcl2 and enhanced oxidant injury [3].
• ATF3 also repressed ATF4-mediated transactivation and arsenite-induced activation of the Gadd153 promoter [1].
• Our results showed that Abeta could not trigger UPR signalings including phosphorylation of PERK, alternative cleavage of xbp-1 mRNA and induction of transcription of xbp-1 and Gadd153 [5].

Anatomical context of Ddit3

• Additional support for this hypothesis was provided by experiments with Rat1 fibroblasts in which conditional expression of Gadd153 conferred increased sensitivity to H(2)O(2) [4].
• 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 [1].

Other interactions of Ddit3

• Additional experiments implicated the PERK/eIF-2 alpha signaling pathway as a contributor to the higher Gadd153 expression and JNK activation, and greater sensitivity of old cells to ER stress [6].

References