title: X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes.
abstract: The unfolded protein response (UPR) is triggered to assist protein folding when endoplasmic reticulum (ER) function is impaired. Recent studies demonstrated that ER stress can also induce cell-specific genes. In this study, we examined whether X-box binding protein 1 (XBP1), a major UPR-linked transcriptional factor, regulates the expression of brain natriuretic peptide (BNP) in cardiomyocytes. In samples from failing human hearts, extensive splicing of XBP1 was observed along with increased expression of glucose-regulated protein of 78 kDa (GRP78), a target of spliced XBP1 (sXBP1), suggesting that the UPR was induced in heart failure in humans. Interestingly, quantitative real-time PCR revealed a positive correlation between cardiac expression of GRP78 and BNP, leading us to test the hypothesis that sXBP1 regulates BNP as well as GRP78 in cardiomyocytes. A pharmacological ER stressor caused a dose-dependent increase in the expression of sXBP1 and BNP by cultured cardiomyocytes. Short interfering RNA targeting XBP1 suppressed the induction of BNP expression by a pharmacological ER stressor or norepinephrine, which was rescued by the adenovirus-mediated overexpression of sXBP1. The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. Direct binding of sXBP1 to this element was confirmed by the chromatin immunoprecipitation assay. These findings suggest that ER stress observed in failing hearts regulates cardiac BNP expression through a novel promoter region of the AP1/CRE-like element.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Sawada
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Hai Ying
authors.initials: HY
authors.lastname: Fu
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Asai
authors.forename: Keiji
authors.initials: K
authors.lastname: Okuda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Isomura
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Asano
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Okada
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsukamoto
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal / Q000379:methods; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology*; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C051684:GRP78 protein, rat; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D000071701:Regulatory Factor X Transcription Factors; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605545:Xbp1 protein, rat; D020097:Natriuretic Peptide, Brain