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Text
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<a href="http://doi.org/10.1074/jbc.M111.274514" target="_blank" rel="noreferrer noopener">http://doi.org/10.1074/jbc.M111.274514</a>
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Pages
41972-41984
Issue
49
Volume
286
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Title
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Curcumin Differentially Regulates Endoplasmic Reticulum Stress through Transcriptional Corepressor SMILE (Small Heterodimer Partner-interacting Leucine Zipper Protein)-mediated Inhibition of CREBH (cAMP Responsive Element-binding Protein H)
Publisher
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Journal of Biological Chemistry
Date
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2011
2011-12
Subject
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phosphorylation; cells; Biochemistry & Molecular Biology; gene-expression; er stress; kinase; atf6; creb/atf-family; hepatic gluconeogenesis; lkb1; zhangfei
Creator
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Misra J; Chanda D; Kim D K; Li T G; Koo S H; Back S H; Chiang J Y L; Choi H S
Description
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Curcumin (diferuloylmethane), a major active component of turmeric (Curcuma longa), is a natural polyphenolic compound. Herein the effect of curcumin on endoplasmic reticulum (ER) stress responsive gene expression was investigated. We report that curcumin induces transcriptional corepressor small heterodimer partner-interacting leucine zipper protein (SMILE) gene expression through liver kinase B1 (LKB1)/adenosine monophosphate-activated kinase (AMPK) signaling pathway and represses ER stress-responsive gene transcription in an ER-bound transcription factor specific manner. cAMP responsive element-binding protein H (CREBH) and activating transcription factor 6 (ATF6) are both ER-bound bZIP family transcription factors that are activated upon ER stress. Of interest, we observed that both curcumin treatment and SMILE overexpression only represses CREBH-mediated transactivation of the target gene but not ATF6-mediated transactivation. Knockdown of endogenous SMILE significantly releases the inhibitory effect of curcumin on CREBH transactivation. Intrinsic repressive activity of SMILE is observed in the Gal4 fusion system, and the intrinsic repressive domain is mapped to the C terminus of SMILE spanning amino acid residues 203-269, corresponding to the basic region leucine zipper (bZIP) domain. In vivo interaction assay revealed that through its bZIP domain, SMILE interacts with CREBH and inhibits its transcriptional activity. Interestingly, we observed that SMILE does not interact with ATF6. Furthermore, competition between SMILE and the coactivator peroxisome proliferator-activated receptor alpha (PGC1 alpha) on CREBH transactivation has been demonstrated in vitro and in vivo. Finally, chromatin immunoprecipitation assays revealed that curcumin decreases the binding of PGC-1 alpha and CREBH on target gene promoter in a SMILE-dependent manner. Overall, for the first time we suggest a novel phenomenon that the curcumin/LKB1/AMPK/SMILE/PGC1 alpha pathway differentially regulates ER stress-mediated gene transcription.
Identifier
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<a href="http://doi.org/10.1074/jbc.M111.274514" target="_blank" rel="noreferrer noopener">10.1074/jbc.M111.274514</a>
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Journal Article or Conference Abstract Publication
2011
atf6
Back S H
Biochemistry & Molecular Biology
Cells
Chanda D
Chiang J Y L
Choi H S
creb/atf-family
er stress
gene-expression
hepatic gluconeogenesis
Journal Article or Conference Abstract Publication
Journal of Biological Chemistry
Kim D K
Kinase
Koo S H
Li T G
lkb1
Misra J
Phosphorylation
zhangfei