title: The role of Bach1 in ultraviolet A-mediated human heme oxygenase 1 regulation in human skin fibroblasts.
abstract: Up-regulation of heme oxygenase 1 (HO-1) by ultraviolet A (UVA; 320-380 nm) irradiation of human skin cells protects them against oxidative stress. The role of Nrf2 in up-regulation of HO-1 and other phase II genes is well established. The mechanism underlying Bach1-mediated HO-1 repression is less well understood although cellular localization seems to be crucial. Because prolonged HO-1 overexpression is likely to be detrimental, it is crucial that activation of the gene is transient. We now show that UVA irradiation of cultured human skin fibroblasts enhances accumulation of Bach1 mRNA and protein severalfold. Endogenous Bach1 protein accumulates in the nucleus after 8h and may occupy MARE sites after HO-1 activation thus providing a compensatory mechanism to control HO-1 overexpression. Overexpression of Bach1, together with MafK, represses basal and UVA-mediated HO-1 protein expression, whereas silencing of the Bach1 gene by Bach1-specific siRNAs causes robust enhancement of constitutive HO-1 levels. UVA treatment of cells in which Bach1 has been silenced leads to higher levels of induction of the HO-1 protein. Although Bach1 protein is exported from the nucleus 12h after UVA irradiation, the release of free cellular heme from microsomal heme-containing proteins is immediate rather than delayed. Although heme does promote the export of Bach1 via the Crm1/exportin 1 pathway and is involved in the delayed UVA-mediated export of the protein, it is not clear how this occurs.
authors: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors: Chintan M
authors: CM
authors: Raval
authors: Julia Li
authors: JL
authors: Zhong
authors: Stephen A
authors: SA
authors: Mitchell
authors: Rex M
authors: RM
authors: Tyrrell
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism*; D006418:Heme / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000528:radiation effects; D010957:Plasmids; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects*; D012867:Skin / Q000166:cytology / Q000201:enzymology* / Q000528:radiation effects; D014162:Transfection; D014466:Ultraviolet Rays; D000097606:Exportin 1 Protein
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D049452:Green Fluorescent Proteins; D006418:Heme; D051547:Heme Oxygenase-1; D028884:Karyopherins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C102108:BACH1 protein, human