Reprogramming of keratin biosynthesis by sulforaphane restores skin integrity in epidermolysis bullosa simplex

Michelle L. Kerns, Daryle DePianto, Albena T. Dinkova-Kostova, Paul Talalay (Lead / Corresponding author), Pierre A. Coulombe (Lead / Corresponding author)

Research output: Contribution to journalArticle

66 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)14460-14465
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number36
DOIs
Publication statusPublished - 4 Sep 2007

Fingerprint

Epidermolysis Bullosa Simplex
Keratins
Skin
Keratinocytes
Intermediate Filaments
Epidermis
Keratin-14
Keratin-5
Mutation
Biological Products
Genes
Transcription Factors
sulforafan
Pharmacology
Wounds and Injuries

Keywords

  • Gli2
  • Keratin 14 null
  • Keratin 17
  • NQO1
  • Nrf2

Cite this

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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.",
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Reprogramming of keratin biosynthesis by sulforaphane restores skin integrity in epidermolysis bullosa simplex. / Kerns, Michelle L.; DePianto, Daryle; Dinkova-Kostova, Albena T.; Talalay, Paul (Lead / Corresponding author); Coulombe, Pierre A. (Lead / Corresponding author).

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 36, 04.09.2007, p. 14460-14465.

Research output: Contribution to journalArticle

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