title: Reprogramming of keratin biosynthesis by sulforaphane restores skin integrity in epidermolysis bullosa simplex.
abstract: Epidermolysis bullosa simplex (EBS) is a rare inherited condition in which the epidermis loses its integrity after mechanical trauma. EBS is typified by the dysfunction of intermediate filaments in basal keratinocytes of epidermis. Most cases of EBS are due to mutations in the keratin 5 or 14 gene (K5 and K14), whose products copolymerize to form intermediate filaments in basal keratinocytes. Available treatments for this disorder are only palliative. Here we exploit functional redundancy within the keratin gene family as the basis for therapy. We show that genetic activation of Gli2 or treatment with a pharmacological activator of Nrf2, two transcription factors eliciting distinct transcriptional programs, alleviates the blistering caused by a K14 deficiency in an EBS mouse model, correlating with K17 induction in basal epidermal keratinocytes. Nrf2 induction is brought about by treatment with sulforaphane, a natural product. Sulforaphane thus represents an attractive option for the prevention of skin blistering associated with K14 mutations in EBS.
authors.affiliation: Department of Biological Chemistry, 725 North Wolfe Street, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Kerns
authors.forename: Daryle
authors.initials: D
authors.lastname: DePianto
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.forename: Paul
authors.initials: P
authors.lastname: Talalay
authors.forename: Pierre A
authors.initials: PA
authors.lastname: Coulombe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001768:Blister / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016110:Epidermolysis Bullosa Simplex / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D017879:Isothiocyanates; D007633:Keratins / Q000096:biosynthesis* / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D013454:Sulfoxides; D013861:Thiocyanates / Q000627:therapeutic use*; D000075746:Zinc Finger Protein Gli2
chemical_list: C000618551:Gli2 protein, mouse; D017879:Isothiocyanates; D051741:Kruppel-Like Transcription Factors; D013454:Sulfoxides; D013861:Thiocyanates; D000075746:Zinc Finger Protein Gli2; D007633:Keratins; C016766:sulforaphane