TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death.

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Citation

Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H

TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death.

EMBO J. 2005 Mar 23;24(6):1243-55. Epub 2005 Mar 10.

PubMed ID
15775988 [ View in PubMed
]
Abstract

C/EBP homologous protein (CHOP) is a stress-inducible nuclear protein that is crucial for the development of programmed cell death and regeneration; however, the regulation of its function has not been well characterized. Slbo, a Drosophila homolog of C/EBP (CCAAT/enhancer binding protein), was shown to be unstabilized by tribbles. Here, we identified TRB3 as a tribbles ortholog in humans, which associated with CHOP to suppress the CHOP-dependent transactivation. TRB3 is induced by various forms endoplasmic reticulum (ER) stress later than CHOP. Tunicamycin treatment enhanced the TRB3 promoter activity, while dominant-negative forms of CHOP suppressed the tunicamycin-induced activation. In addition, the tunicamycin response region in the TRB3 promoter contains amino-acid response elements overlapping the CHOP-binding site, and CHOP and ATF4 cooperated to activate this promoter activity. Knockdown of endogenous ATF4 or CHOP expression dramatically repressed tunicamycin-induced TRB3 induction. Furthermore, knockdown of TRB3 expression decreased ER stress-dependent cell death. These results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions, and that it is involved in CHOP-dependent cell death during ER stress.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Cyclic AMP-dependent transcription factor ATF-4P18848Details