title: Two in-and-out modulation strategies for endoplasmic reticulum stress-linked gene expression of pro-apoptotic macrophage-inhibitory cytokine 1.
abstract: Excessive and persistent insults during endoplasmic reticulum (ER) stress lead to apoptotic cell death that is implicated in a range of chronic inflammatory diseases and cancers. Macrophage inhibitory cytokine 1 (MIC-1), a member of the transforming growth factor-β superfamily, is diversely linked to the pathogenesis of cancer. To investigate the precise molecular mechanisms of MIC-1 gene regulation, ER stress and its related signals were studied in human colon cancer cells. Functionally, MIC-1 played pivotal roles in ER stress-linked apoptotic death, which was also influenced by C/EBP homologous protein, a well known apoptotic mediator of ER stress. ER stress enhanced MIC-1 mRNA stability instead of transcriptional activation, and there were two mechanistic translocations critical for mRNA stabilization. First, C/EBP homologous protein triggered protein kinase C-linked cytosolic translocation of the HuR/ELAVL1 (Elav-like RNA-binding protein 1) RNA-binding protein, which bound to and stabilized MIC-1 transcript. As the second critical in-and-out regulation, ER stress-activated ERK1/2 signals contributed to enhanced stabilization of MIC-1 transcript by controlling the extended holding of the nucleated mRNA in the stress granules fusing with the mRNA-decaying processing body. We propose that these two sequential in-and-out modulations can account for stabilized transcription and subsequent translation of pro-apoptotic MIC-1 gene in human cancer cells under ER stress.
authors.affiliation: Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Choi
authors.forename: Hyun
authors.initials: H
authors.lastname: Yang
authors.forename: Kee Hun
authors.initials: KH
authors.lastname: Do
authors.forename: Juil
authors.initials: J
authors.lastname: Kim
authors.forename: Hyun-Hong
authors.initials: HH
authors.lastname: Kim
authors.forename: Heejeong
authors.initials: H
authors.lastname: Lee
authors.forename: Chang Gyu
authors.initials: CG
authors.lastname: Oh
authors.forename: Dong Won
authors.initials: DW
authors.lastname: Lee
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
mesh_terms: D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism; D000067780:ELAV-Like Protein 1; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D055436:Growth Differentiation Factor 15 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051742:Transcription Factor CHOP; D011493:Protein Kinase C