DDIT3 Research Reagents

DDIT3 Background

DNA damage-inducible transcript 3 (DDIT3), also called C/EBP homologous protein (CHOP), is an endoplasmic reticulum (ER) stress-inducible protein that belongs to a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors ^[1][2]. DDIT3/CHOP functions as a multifunctional transcription factor that contributes to cellular functions, including apoptosis, autophagy, inflammation, cell differentiation, and proliferation. DDIT3/CHOP possesses N-terminal transcriptional activation/repression domains necessary for its proteasomal degradation and a C-terminal basic-leucine zipper (bZIP) domain, including a basic region for DNA binding and a leucine zipper motif for dimerization ^[3]. A serine/threonine-rich motif in the transactivation domain of DDIT3/CHOP can be recognized by speckle-type POZ protein (SPOP), which triggers DDIT3/CHOP degradation via the ubiquitin-proteasome pathway ^[4]. TRB3 antagonized p300 binding to CHOP via its N-terminal domain ^[5]. Degradation of CHOP protein through the N-terminal domain was inhibited by treatment with trichostatin A (TSA) ^[5]. During ER stress, CHOP is mainly induced via activation of the PERK (ER-localized kinase double-stranded RNA-activated protein kinase (PKR)-like ER kinase) through the downstream phosphorylation of a translation initiation factor, eukaryotic initiation factor 2α (eIF2α), and induction of a transcription factor, activation transcription factor 4 (ATF4) ^[6]. Apoptosis ensues by ATF4-CHOP-mediated induction of several pro-apoptotic genes and suppression of the synthesis of anti-apoptotic Bcl-2 proteins ^[7]. Also, Oyadomari, S. and Mori, M. demonstrated that CHOP-mediated apoptosis during ER stress is involved in diseases with ER stress-dependent cell death, such as neurodegenerative disease and/or type I diabetes ^[8]. During amino acid limitation and ER stress, CHOP binds to the promoters of a set of autophagy genes ^[9]. WafaB'chir and his colleagues showed that during the first 6 h of starvation, CHOP upregulates numerous autophagy genes but is not involved in the first steps of the autophagic process. When the amino acid starvation is prolonged (16–48 h), CHOP exhibits a dual role in both inducing apoptosis and limiting autophagy through the transcriptional control of specific genes ^[10]. CHOP is also implicated in adipogenesis and erythropoiesis.

[1] Fornace, A. J., Nebert, D. et al. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents [J]. Mol. Cell. Biol. 1989, 9, 4196–4203.
[2] Lekstrom-Himes J. and Xanthopoulos K. G. Biological role of the CCAAT/enhancer-binding protein family of transcription factors [J]. J. Biol. Chem. 1998, 273, 28545–28548.
[3] Ubeda M, Wang XZ, et al. Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element [J]. Molecular and Cellular Biology. 1996, 16 (4): 1479–89.
[4] Zhang P, Gao K, et al. Destruction of DDIT3/CHOP protein by wild-type SPOP but not prostate cancer-associated mutants [J]. Hum Mutat (2014) 35(9):1142–51.
[5] Nobumichi Ohoka, Takayuki Hattori, et al. Critical and Functional Regulation of CHOP (C/EBP Homologous Protein) through the N-terminal Portion [J]. The Journal of Biological Chemistry 2007, 282, 35687-35694.
[6] Harding, H. P., Novoa, I., et al. Regulated translation initiation controls stress-induced gene expression in mammalian ce[J]. Mol. Cell 200o, 6, 1099–1108.
[7] W Rozpedek, D Pytel, et al. The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress [J]. Curr Mol Med, 2016, 16 (6), 533-44.
[8] Oyadomari, S., and Mori, M. Roles of CHOP/GADD153 in endoplasmic reticulum stress[J]. Cell Death Differ. 2004, 11, 381–389.
[9] B’Chir W, Maurin AC, et al. The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression [J]. Nucleic Acids Res (2013) 41(16):7683–99.
[10] WafaB'chir, Cédric Chaveroux, et al. Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation [J]. Volume 26, Issue 7, July 2014, Pages 1385-1391.