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Gene Review

Ddit3  -  DNA-damage inducible transcript 3

Rattus norvegicus

Synonyms: C/EBP zeta, C/EBP-homologous protein, C/EBP-homologous protein 10, CCAAT/enhancer-binding protein homologous protein, CHOP, ...
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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].


  1. 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. Fawcett, T.W., Martindale, J.L., Guyton, K.Z., Hai, T., Holbrook, N.J. Biochem. J. (1999) [Pubmed]
  2. Growth arrest and DNA damage-inducible gene 153 increases transiently in the thalamus following focal cerebral infarction. Onoue, S., Kumon, Y., Igase, K., Ohnishi, T., Sakanaka, M. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  3. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. McCullough, K.D., Martindale, J.L., Klotz, L.O., Aw, T.Y., Holbrook, N.J. Mol. Cell. Biol. (2001) [Pubmed]
  4. Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells to oxidant injury. Ikeyama, S., Wang, X.T., Li, J., Podlutsky, A., Martindale, J.L., Kokkonen, G., van Huizen, R., Gorospe, M., Holbrook, N.J. J. Biol. Chem. (2003) [Pubmed]
  5. Beta-amyloid peptides induces neuronal apoptosis via a mechanism independent of unfolded protein responses. Yu, M.S., Suen, K.C., Kwok, N.S., So, K.F., Hugon, J., Chuen-Chung Chang, R. Apoptosis (2006) [Pubmed]
  6. Elevated gadd153/chop expression and enhanced c-Jun N-terminal protein kinase activation sensitizes aged cells to ER stress. Li, J., Holbrook, N.J. Exp. Gerontol. (2004) [Pubmed]
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