title: 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).
abstract: 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 α (PGC-1α) on CREBH transactivation has been demonstrated in vitro and in vivo. Finally, chromatin immunoprecipitation assays revealed that curcumin decreases the binding of PGC-1α 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/PGC1α pathway differentially regulates ER stress-mediated gene transcription.
authors: Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Science and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors: Jagannath
authors: J
authors: Misra
authors: Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Science and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors: Dipanjan
authors: D
authors: Chanda
authors: Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Science and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors: Don-Kyu
authors: DK
authors: Kim
authors: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272.
authors: Tiangang
authors: T
authors: Li
authors: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Republic of Korea.
authors: Seung-Hoi
authors: SH
authors: Koo
authors: School of Biological Sciences, University of Ulsan, Ulsan 680-749, South Korea.
authors: Sung-Hoon
authors: SH
authors: Back
authors: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272.
authors: John Y L
authors: JYL
authors: Chiang
authors: Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Science and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea; Research Institute of Medical Sciences, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea. Electronic address: hsc@chonnam.ac.kr.
authors: Hueng-Sik
authors: HS
authors: Choi
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D003474:Curcumin / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000975:Antioxidants; C497112:Atf6 protein, mouse; C497113:Atf6 protein, rat; D050976:Basic-Leucine Zipper Transcription Factors; C411104:CREBZF protein, human; C570110:Crebzf protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; C570109:SMILE protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D003474:Curcumin