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    Haem repression of the housekeeping 5-aminolaevulinic acid synthase gene in the hepatoma cell line LMH

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    Authors
    Kolluri, Sridevi
    Sadlon, Timothy J.
    May, Brian K.
    Bonkovsky, Herbert L.
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Graduate School of Biomedical Sciences
    Document Type
    Journal Article
    Publication Date
    2005-07-22
    Keywords
    5-Aminolevulinate Synthetase; Animals; Cell Line, Tumor; Chickens; Down-Regulation; Drug Synergism; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutethimide; Heme; Heptanoates; Promoter Regions (Genetics); Up-Regulation
    Life Sciences
    Medicine and Health Sciences
    
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    Link to Full Text
    http://dx.doi.org/10.1042/BJ20050354
    Abstract
    Haem is essential for the health and function of nearly all cells. 5-Aminolaevulinic acid synthase-1 (ALAS-1) catalyses the first and rate-controlling step of haem biosynthesis. ALAS-1 is repressed by haem and is induced strongly by lipophilic drugs that also induce CYP (cytochrome P450) proteins. We investigated the effects on the avian ALAS-1 gene promoter of a phenobarbital-like chemical, Glut (glutethimide), and a haem synthesis inhibitor, DHA (4,6-dioxoheptanoic acid), using a reporter gene assay in transiently transfected LMH (Leghorn male hepatoma) hepatoma cells. A 9.1 kb cALAS-1 (chicken ALAS-1) promoter-luciferase-reporter construct, was poorly induced by Glut and not by DHA alone, but was synergistically induced by the combination. In contrast, a 3.5 kb promoter ALAS-1 construct was induced by Glut alone, without any further effect of DHA. In addition, exogenous haem (20 microM) repressed the basal and Glut- and DHA-induced activity of luciferase reporter constructs containing 9.1 and 6.3 kb of ALAS-1 5'-flanking region but not the construct containing the first 3.5 kb of promoter sequence. This effect of haem was subsequently shown to be dependent on the -6.3 to -3.5 kb region of the 5'-flanking region of cALAS-1 and requires the native orientation of the region. Two deletion constructs of this approx. 2.8 kb haem-repressive region (1.7 and 1.1 kb constructs) retained haem-dependent repression of basal and drug inductions, suggesting that more than one cis-acting elements are responsible for this haem-dependent repression of ALAS-1. These results demonstrate that there are regulatory regions in the 5'-flanking region of the cALAS-1 gene that respond to haem and provide a basis for further investigations of the molecular mechanisms by which haem down-regulates expression of the ALAS-1 gene.
    Source
    Biochem J. 2005 Nov 15;392(Pt 1):173-80. Link to article on publisher's site
    DOI
    10.1042/BJ20050354
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/33965
    PubMed ID
    16033334
    Related Resources
    Link to article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1042/BJ20050354
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