title: Mithramycin reduces expression of fibro-proliferative mRNAs in human gingival fibroblasts.
abstract: Fibrosis is characterized by loss of normal structure and function of a tissue or organ resulting from excessive fibroblast proliferation and extracellular matrix production. Currently, there is no efficient treatment for fibrosis. Herein, we test effects of the drug mithramycin, which targets the Sp1 family of transcription factors, on mRNA expression by human gingival fibroblasts. Mithramycin reduced expression of connective tissue growth factor and type I collagen mRNAs. Microarray profiling revealed that mithramycin selectively blocked expression of cell proliferation and transforming growth factor-beta (TGF-β) signalling clusters. These microarray data were validated using real-time polymerase chain reaction and western blot analyses. Mithramycin suppressed expression of key profibrotic TGF-β signalling mediators, Smad3 and p300, as well as cell proliferation. Taken together, these data suggest that the Sp1 family of transcription factors may contribute to expression of fibrogenic genes in human gingival fibroblasts; drugs targeting the Sp1 family may be beneficial in treatment of fibro-proliferative diseases.
authors.affiliation: Department of Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: O A
authors.initials: OA
authors.lastname: Fajardo
authors.forename: K
authors.initials: K
authors.lastname: Thompson
authors.forename: S K
authors.initials: SK
authors.lastname: Parapuram
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Leask
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005881:Gingiva / Q000166:cytology*; D006801:Humans; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D008926:Plicamycin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D051900:Smad3 Protein; D016329:Sp1 Transcription Factor; D016212:Transforming Growth Factor beta; D050880:p300-CBP Transcription Factors; D008926:Plicamycin