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Gene Review

Ddit3  -  DNA-damage inducible transcript 3

Mus musculus

Synonyms: C/EBP homoologous protein 10, C/EBP zeta, C/EBP-homologous protein, C/EBP-homologous protein 10, CCAAT/enhancer-binding protein homologous protein, ...
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Disease relevance of Ddit3


Psychiatry related information on Ddit3

  • We suggest that CHOP-10 is a negative modulator of the activity of C/EBP-like proteins in certain terminally differentiated cells, similar to the regulatory function of Id on the activity of MyoD and MyoD-related proteins important in the development of muscle cells [4].

High impact information on Ddit3

  • CHOP-10 is induced upon differentiation of 3T3-L1 fibroblasts to adipocytes, and cytokine-induced dedifferentiation of adipocytes is preceded by the loss of nuclear CHOP-10 [4].
  • Thus, heterodimers of CHOP-10 and C/EBP-like proteins are unable to bind their cognate DNA enhancer element [4].
  • Coimmunoprecipitation of CHOP-10 and LAP from transfected COS-1 cells demonstrated a direct interaction between the two proteins, in vivo [4].
  • A 32P-labeled LAP DNA-binding and dimerization domain "zipper probe" was used to isolate a clone that encodes a new C/EBP-homologous protein: CHOP-10 [4].
  • We conclude that ER overload in beta cells causes ER stress and leads to apoptosis via Chop induction [5].

Chemical compound and disease context of Ddit3

  • Gadd45 and Gadd153 messenger RNA levels are increased during hypoxia and after exposure of cells to agents which elevate the levels of the glucose-regulated proteins [1].
  • Hypoxia (1% O2) strongly increased reactive oxygen species generation, hypoxia-inducible factor-1 and CHOP-10/GADD153 expression, and inhibited adipocyte differentiation [6].

Biological context of Ddit3

  • Role of C/EBP homologous protein (CHOP-10) in the programmed activation of CCAAT/enhancer-binding protein-beta during adipogenesis [7].
  • In support of these findings, up-regulation of CHOP-10 with the protease inhibitor N-acetyl-Leu-Leu-norleucinal prevents activation of C/EBPbeta, expression of C/EBPalpha, and adipogenesis [7].
  • As preadipocytes reach S phase, CHOP-10 is down-regulated, apparently releasing C/EBPbeta from inhibitory constraint and allowing transactivation of the C/EBPalpha gene [7].
  • The absence of P58(IPK) resulted in increased expression levels of two ER stress-inducible genes, BiP and Chop, consistent with the enhanced eIF2alpha phosphorylation in the P58(IPK) deletion cells [8].
  • Accordingly, CHOP10, a transcription factor induced early in response to ER stress, and the pleiotropic Clusterin, involved in protein folding, were also overexpressed [9].

Anatomical context of Ddit3


Associations of Ddit3 with chemical compounds


Regulatory relationships of Ddit3

  • Dominant-negative CHOP-10 is initially expressed by growth-arrested preadipocytes and sequesters/inactivates C/EBPbeta by heterodimerization with its leucine zipper [15].
  • Moreover, an exaggerated Gadd153 response to stress induced by ER stress agents was observed in PS1 mutant cells [16].
  • We now report that Epo markedly upregulates chop (gadd153) expression and that this transcription factor plays a role in erythropoiesis [17].

Other interactions of Ddit3

  • The induction of caspase-11 by LPS was suppressed in Chop knockout mice [18].
  • Focusing on this latter event highlights Ddit3, Timm8b and Oazin as potential new injury-induced molecular actors involved in a stress response pathway [19].
  • Urea treatment (100-300 mM) increased expression of the oxidative stress-responsive transcription factor, Gadd153/CHOP, at the mRNA and protein levels (at >/=4 h) in renal medullary mIMCD3 cells in culture, whereas other solutes did not [12].
  • An abnormality in the translational regulation of Gadd153 may sensitize cells to the detrimental effects of ER stress and contribute to the pathogenic actions of PS1 mutations in FAD [16].
  • The accumulation of p53, induction of p21, gadd45, and gadd153, and arrest of the cell cycle in G1 and G2 occurred normally [20].

Analytical, diagnostic and therapeutic context of Ddit3


  1. Gadd45 and Gadd153 messenger RNA levels are increased during hypoxia and after exposure of cells to agents which elevate the levels of the glucose-regulated proteins. Price, B.D., Calderwood, S.K. Cancer Res. (1992) [Pubmed]
  2. Upregulation of CHOP-10 (gadd153) expression in the mouse blastocyst as a response to stress. Fontanier-Razzaq, N.C., Hay, S.M., Rees, W.D. Mol. Reprod. Dev. (1999) [Pubmed]
  3. Heat-inducible TNF-alpha gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy. Ito, A., Shinkai, M., Honda, H., Kobayashi, T. Cancer Gene Ther. (2001) [Pubmed]
  4. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Ron, D., Habener, J.F. Genes Dev. (1992) [Pubmed]
  5. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. Oyadomari, S., Koizumi, A., Takeda, K., Gotoh, T., Akira, S., Araki, E., Mori, M. J. Clin. Invest. (2002) [Pubmed]
  6. Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation: a mechanism for hypoxia-dependent effect. Carrière, A., Carmona, M.C., Fernandez, Y., Rigoulet, M., Wenger, R.H., Pénicaud, L., Casteilla, L. J. Biol. Chem. (2004) [Pubmed]
  7. Role of C/EBP homologous protein (CHOP-10) in the programmed activation of CCAAT/enhancer-binding protein-beta during adipogenesis. Tang, Q.Q., Lane, M.D. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  8. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Yan, W., Frank, C.L., Korth, M.J., Sopher, B.L., Novoa, I., Ron, D., Katze, M.G. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  9. Trefoil factor 1 (TFF1/pS2) deficiency activates the unfolded protein response. Torres, L.F., Karam, S.M., Wendling, C., Chenard, M.P., Kershenobich, D., Tomasetto, C., Rio, M.C. Mol. Med. (2002) [Pubmed]
  10. The growth arrest genes gas5, gas6, and CHOP-10 (gadd153) are expressed in the mouse preimplantation embryo. Fleming, J.V., Fontanier, N., Harries, D.N., Rees, W.D. Mol. Reprod. Dev. (1997) [Pubmed]
  11. Geldanamycin, an hsp90/GRP94-binding drug, induces increased transcription of endoplasmic reticulum (ER) chaperones via the ER stress pathway. Lawson, B., Brewer, J.W., Hendershot, L.M. J. Cell. Physiol. (1998) [Pubmed]
  12. Urea-associated oxidative stress and Gadd153/CHOP induction. Zhang, Z., Yang, X.Y., Cohen, D.M. Am. J. Physiol. (1999) [Pubmed]
  13. Regulation of the C/EBP-related gene gadd153 by glucose deprivation. Carlson, S.G., Fawcett, T.W., Bartlett, J.D., Bernier, M., Holbrook, N.J. Mol. Cell. Biol. (1993) [Pubmed]
  14. Evidence for distinct kinase-mediated pathways in gadd gene responses. Carrier, F., Zhan, Q., Alamo, I., Hanaoka, F., Fornace, A.J. Biochem. Pharmacol. (1998) [Pubmed]
  15. Effect of serum on the down-regulation of CHOP-10 during differentiation of 3T3-L1 preadipocytes. Huang, H., Lane, M.D., Tang, Q.Q. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  16. Involvement of Gadd153 in the pathogenic action of presenilin-1 mutations. Milhavet, O., Martindale, J.L., Camandola, S., Chan, S.L., Gary, D.S., Cheng, A., Holbrook, N.J., Mattson, M.P. J. Neurochem. (2002) [Pubmed]
  17. Regulated expression and functional role of the transcription factor CHOP (GADD153) in erythroid growth and differentiation. Coutts, M., Cui, K., Davis, K.L., Keutzer, J.C., Sytkowski, A.J. Blood (1999) [Pubmed]
  18. C/EBP Homologous Protein (CHOP) Is Crucial for the Induction of Caspase-11 and the Pathogenesis of Lipopolysaccharide-Induced Inflammatio. Endo, M., Mori, M., Akira, S., Gotoh, T. J. Immunol. (2006) [Pubmed]
  19. Gene profiling during development and after a peripheral nerve traumatism reveals genes specifically induced by injury in dorsal root ganglia. Méchaly, I., Bourane, S., Piquemal, D., Al-Jumaily, M., Ventéo, S., Puech, S., Scamps, F., Valmier, J., Carroll, P. Mol. Cell. Neurosci. (2006) [Pubmed]
  20. DNA-dependent protein kinase is not required for accumulation of p53 or cell cycle arrest after DNA damage. Rathmell, W.K., Kaufmann, W.K., Hurt, J.C., Byrd, L.L., Chu, G. Cancer Res. (1997) [Pubmed]
  21. cDNA microarray analysis reveals chop-10 plays a key role in Sertoli cell injury induced by bisphenol A. Tabuchi, Y., Kondo, T. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
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