TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death.
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.
Ohoka
Nobumichi
N
Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya, Japan.
Yoshii
Satoshi
S
Hattori
Takayuki
T
Onozaki
Kikuo
K
Hayashi
Hidetoshi
H
D051701:Activating Transcription Factor 4; D000595:Amino Acid Sequence; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D012097:Repressor Proteins; D020218:Response Elements / Q000235:genetics; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014415:Tunicamycin / Q000494:pharmacology
C497109:ATF4 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; D018797:Cell Cycle Proteins; C497249:DDIT3 protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D014157:Transcription Factors; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D017346:Protein Serine-Threonine Kinases