Critical and functional regulation of CHOP (C/EBP homologous protein) through the N-terminal portion.
C/EBP homologous protein (CHOP) is an endoplasmic reticulum stress-inducible protein that plays a critical role in the regulation of programmed cell death; however, the regulation of its function has not been well characterized. We have previously demonstrated that CHOP is regulated by the ubiquitin-proteasome system. In this study, during the process of clarifying the mechanism of the degradation of CHOP, we identified a novel regulation domain of CHOP in its N-terminal portion that is involved in various regulations and functions. The CHOP N-terminal domain is necessary not only for protein degradation but also for its transactivity and interaction with p300. In addition, trichostatin A, a histone deacetylase inhibitor, repressed the degradation of CHOP protein via the N-terminal domain. TRB3, a mammalian tribbles homolog that functions as a repressor of CHOP, also interacted with CHOP via the N-terminal portion and significantly blocked the association of p300 with CHOP. These results suggest that the N-terminal portion of CHOP plays a crucial role in its functional regulation and enable us to identify a novel function of TRB3 as an intracellular antagonist of the p300-binding domain of CHOP.
Ohoka
Nobumichi
N
Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
Hattori
Takayuki
T
Kitagawa
Masatoshi
M
Onozaki
Kikuo
K
Hayashi
Hidetoshi
H
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000037:antagonists & inhibitors; D017434:Protein Structure, Tertiary / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; C497249:DDIT3 protein, human; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D025801:Ubiquitin; D051742:Transcription Factor CHOP; C012589:trichostatin A; D050880:p300-CBP Transcription Factors; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases