Disease relevance of DDIT3

• The FUS gene at 16p11 fuses with DDIT3 and ATF1 as the result of translocations with chromosome band 12q13 in myxoid liposarcoma and angiomatoid fibrous histiocytoma, respectively, and with ERG as the result of a t(16;21)(p11;q22) in acute myeloid leukemia [1].
• In order to investigate the downstream targets of DDIT3, and the transforming effects of the FUS-DDIT3 fusion protein, we have introduced DDIT3-GFP and FUS-DDIT3-GFP constructs into a human fibrosarcoma cell line [2].
• Expression of DOL54 is not restricted to myxoid liposarcomas with the FUS-DDIT3 chimera but is found in various sarcomas [3].
• Previously, we observed that a synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) effectively impaired cell growth and survival (induction of growth arrest and apoptosis) in human hepatoma cells, which was accompanied by over expression of GADD153 [4].
• Green tea polyphenol stimulates cancer preventive effects of celecoxib in human lung cancer cells by upregulation of GADD153 gene [5].

High impact information on DDIT3

• In human myxoid liposarcoma, a chromosomal rearrangement leads to fusion of the growth-arresting and DNA-damage-inducible transcription factor CHOP (GADD153) to a peptide fragment encoded by the TLS gene [6].
• The growth arrest and DNA damage-inducible gene CHOP (GADD153) encodes a small nuclear protein from the C/EBP family, originally isolated from adipocytes in culture [7].
• Furthermore, immunohistochemistry for DDIT3 and ARG2 showed consistent staining for carcinoma in an independent set 59 follicular tumors (estimated concordance, 0.76; 95% confidence interval, [0.59, 0.93]) [8].
• The acetaldehyde-stimulated mitochondrial cholesterol content was preceded by increased levels of endoplasmic reticulum (ER)-responsive gene GADD153 and transcription factor sterol regulatory element-binding protein 1 and mimicked by the ER stress-inducing agents tunicamycin and homocysteine [9].
• Among the members of the GADD family of genes, GADD153, GADD45 alpha, and GADD34 displayed marked, and GADD45 gamma showed minimal induction [10].

Chemical compound and disease context of DDIT3

• GADD153-mediated anticancer effects of N-(4-hydroxyphenyl)retinamide on human hepatoma cells [11].
• In this report we have demonstrated that treatment of rat pheochromocytoma PC12 cells with sodium arsenite leads to enhanced expression of C/EBP-beta and GADD153 (growth arrest and DNA damage inducible gene 153) but not other C/EBPs [12].
• Induction of GADD45 and GADD153 in neuroblastoma cells by dopamine-induced toxicity [13].
• Exposure of mammalian cells to ultraviolet light, nutrient deprived culture media, hypoxia, environmental toxicants such as methyl mercury, methyl methanesulfonate, crocodilite asbestos or the agents that disrupt the function of endoplasmic reticulum (ER) leads to activation of the pro-apoptotic transcription factor GADD153/CHOP [14].
• Curcumin-induced GADD153 gene up-regulation in human colon cancer cells [15].

Biological context of DDIT3

• In addition, development of lipoblasts and the typical MLS/RCLS capillary network could be an effect of the DDIT3 transcription factor partner of the fusion oncogene [16].
• Most MLS/RCLS carry a t(12;16) translocation, resulting in a FUS-DDIT3 fusion gene [16].
• Among them, we further verified that the expression of transferrin (Tf), which is a negative acute-phase protein and is essential to cell survival as a growth factor, was highly modulated by drug-induced GADD153 over expression or by in vitro transfection [4].
• Subtraction cloning analysis identified that troglitazone stimulated expression of the growth arrest and DNA-damage inducible (GADD)153 gene, and the increased expression of GADD153 mRNA was also confirmed by an array analysis of the 160 apoptosis-related genes [17].
• Inhibition of GADD153 gene expression by an antisense phosphorothionate oligonucleotide attenuated the troglitazone-induced growth inhibition [17].

Anatomical context of DDIT3

• The transcription factor CHOP/GADD153 is reportedly induced by cellular stresses such as UV light, genotoxic agents, and protein misfolding in the endoplasmic reticulum [4].
• Troglitazone did not stimulate GADD153 mRNA levels in undifferentiated 3T3-L1 cells lacking PPAR-gamma expression, whereas its induction was clearly observed in differentiated adipocytes expressing PPAR-gamma [17].
• Expression and transactivating functions of the bZIP transcription factor GADD153 in mammary epithelial cells [18].
• Analysis of mouse mammary gland development revealed that GADD153 expression was predominantly restricted in the early lactating stages [18].
• Hydrogen peroxide induces GADD153 in Jurkat cells through the protein kinase C-dependent pathway [19].

Associations of DDIT3 with chemical compounds

• Western blot analysis revealed that troglitazone also increased GADD153 protein levels in a time-dependent manner [17].
• Furthermore, EGCG did not enhance GADD153 gene expression or apoptosis induction in PC-9 cells in combination with N-(4-hydroxyphenyl)retinamide or with aspirin [5].
• Judging by upregulation of GADD153, only cotreatment with EGCG plus celecoxib synergistically induced apoptosis of PC-9 cells [5].
• Activator protein-1 and CCAAT/enhancer-binding protein mediated GADD153 expression is involved in deoxycholic acid-induced apoptosis [20].
• N-Acetyl-l-cysteine or GADD153 antisense significantly protected the cells from 4HPR-induced apoptosis, accompanying by the inhibition of GADD153 overexpression [11].

Physical interactions of DDIT3

• The TLS-CHOP oncoprotein, found in the majority of human myxoid liposarcomas, consists of a fusion between the transcription factor CHOP/GADD153 and the N terminus of an RNA-binding protein TLS/FUS [21].

Regulatory relationships of DDIT3

• The growth arrest- and DNA damage-inducible gene 153 (GADD153) mRNA expression was prominently upregulated by CRP [22].
• Taken together, these results strongly suggest that ATF3 represses the expression of gadd153/Chop10 [23].
• Our results also demonstrate how ETS1 and FLI-1 specifically regulate GADD153 expression [24].
• However, the expression of the pro-apoptotic factor CHOP/GADD153 was induced and caspase-12 was activated in stressed aged rats but not in young animals [25].
• We show that c-Myc represses the expression of GADD45a and GADD153 in response to thapsigargin, a nongenotoxic stress, as well as other endoplasmic reticulum (ER) stress agents. c-Myc represses both the basal expression and the magnitude of ER stress induction of GADD gene transcription [26].

Other interactions of DDIT3

• In conclusion, Tf and other target genes identified may play a functional role in the downstream pathway of GADD153 [4].
• These findings collectively indicated that activation of PPAR-gamma by TZDs could cause growth inhibition and apoptosis of NSCLC cells and that GADD153 might be a candidate factor implicated in these processes [17].
• Activity of the GADD153 promoter occurred in a NSCLC cell line in transient transcription assays and was significantly stimulated by troglitazone, although binding of PPAR/retinoid X receptor heterodimer was not detected in the promoter region in gel retardation assays [17].
• The expression of both GADD45 and GADD153 was increased in two cell lines following oil A treatment [27].
• However, mRNA expression of GADD153 was increased most markedly in DOC-treated HCT-116 colonocytes, which express wild-type p53 [28].

Analytical, diagnostic and therapeutic context of DDIT3

• In addition, the effect of DDIT3 and FUS-DDIT3 on the expression of other acute phase genes was examined using real-time PCR [2].
• We screened 614 sequence-verified clones by Northern blotting, of which 42 genes were scored as over expressed and 17 genes as under expressed in GADD153 transfectants compared with control vector transfectants [4].
• In the present study, we show that Fas receptor ligation or cellular treatment with synthetic C6-ceramide results in activation or phosphorylation, respectively, of the small G-protein Rac1, Jun N-terminal kinase (JNK)/p38 kinases (p38-K), and the transcription factor GADD153 [29].
• Screening of a cDNA microarray chip containing 225 different genes revealed that GADD153 (growth arrest and DNA damage inducible gene), a transcription factor involved in apoptosis, showed the strongest differential expression following celecoxib treatment in all three cervical cancer cell lines [30].
• GADD153 mRNA levels were measured in biopsies obtained before and 24 h after treatment with cDDP from 32 patients with stage III/IV head and neck cancer [31].

References