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. doi: 10.1038/sj.emboj.7600596. Epub 2005 Mar 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4
  • Amino Acid Sequence
  • Apoptosis*
  • Base Sequence
  • Binding Sites
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • CCAAT-Enhancer-Binding Proteins / physiology*
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • Cell Line, Tumor
  • Down-Regulation
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / physiology*
  • Humans
  • Molecular Sequence Data
  • Mutagenesis
  • Promoter Regions, Genetic / genetics
  • Protein Serine-Threonine Kinases
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Repressor Proteins
  • Response Elements / genetics
  • Transcription Factor CHOP
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcription, Genetic
  • Transcriptional Activation*
  • Tunicamycin / pharmacology

Substances

  • ATF4 protein, human
  • CCAAT-Enhancer-Binding Proteins
  • Cell Cycle Proteins
  • DDIT3 protein, human
  • RNA, Small Interfering
  • Repressor Proteins
  • TRIB3 protein, human
  • Transcription Factors
  • Tunicamycin
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • Protein Serine-Threonine Kinases