title: Two conserved regions within the tissue-type plasminogen activator gene promoter mediate regulation by brain-derived neurotrophic factor.
abstract: Tissue-type plasminogen activator (t-PA) has recently been identified as a modulator of neuronal plasticity and can initiate conversion of the pro-form of brain-derived neurotrophic factor (BDNF) into its mature form. BDNF also increases t-PA gene expression implicating t-PA as a downstream effector of BDNF function. Here we demonstrate that BDNF-mediated induction of t-PA mRNA requires an increase in t-PA gene transcription. Reporter constructs harboring 9.5 kb of the human t-PA promoter conferred BDNF-responsiveness in transfected mouse primary cortical neurons. This regulation was recapitulated in HEK 293 cells coexpressing the TrkB neurotrophin receptor. t-PA promoter-deletion analysis revealed the presence of two BDNF-responsive domains, one located between -3.07 and -2.5 kb and the other within the proximal promoter. The upstream region was shown to confer BDNF responsiveness in a TrkB-dependent manner when attached to a heterologous promoter. We also identify homologous regions within the murine and bovine t-PA gene promoters and demonstrate that the equivalent upstream murine sequence functions as a BDNF-responsive enhancer when inserted 5' of the human proximal t-PA promoter. Hence, BDNF-mediated induction of t-PA transcription relies on conserved modular promoter elements including a novel upstream BDNF-responsive domain and the proximal t-PA gene promoter.
authors.affiliation: Monash University, Australian Centre for Blood Diseases, Melbourne, Australia.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Daniel
authors.forename: Wolfram
authors.initials: W
authors.lastname: Lux
authors.forename: Andre L
authors.initials: AL
authors.lastname: Samson
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Schleuning
authors.forename: Be'eri
authors.initials: B
authors.lastname: Niego
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Weiss
authors.forename: Anna
authors.initials: A
authors.lastname: Tjärnlund-Wolf
authors.forename: Robert L
authors.initials: RL
authors.lastname: Medcalf
mesh_terms: D000818:Animals; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D010959:Tissue Plasminogen Activator / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010959:Tissue Plasminogen Activator