Thyroid Hormones and Gamma Interferon Specifically Increase K15 Keratin Gene Transcription

Nada Radoja, Olivera Stojadinovic, Ahmad Waseem, Marjana Tomic-Canic, Vladana Milisavljevic, Susan Teebor, Miroslav Blumenberg

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Basal layers of stratified epithelia express keratins K5, K14, and K15, which assemble into intermediate filament networks. Mutations in K5 or K14 genes cause epidermolysis bullosa simplex (EBS), a disorder with blistering in the basal layer due to cell fragility. Nonkeratinizing stratified epithelia, e.g., in the esophagus, produce more keratin K15 than epidermis, which alleviates the esophageal symptoms in patients with K14 mutations. Hypothesizing that increasing the cellular content of K15 could compensate for the mutant K14 and thus ease skin blistering in K14 EBS patients, we cloned the promoter of the K15 gene and examined its transcriptional regulation. Using cotransfection, gel mobility shifts, and DNase 1 footprinting, we have identified the regulators of K15 promoter activity and their binding sites. We focused on those that can be manipulated with extracellular agents, transcription factors C/EBP, AP-1, and NF-κB, nuclear receptors for thyroid hormone, retinoic acid, and glucocorticoids, and the cytokine gamma interferon (1FN-γ). We found that C/EBP-β and AP-1 induced, while retinoic acid, glucocorticoid receptors, and NF-κB suppressed, the K15 promoter, along with other keratin gene promoters. However, the thyroid hormone and IFN-γ uniquely and potently activated the K15 promoter. Using these agents, we could boost the amounts of K15 in human epidermis. Our findings suggest that treatments based on thyroid hormone and IFN-γ could become effective agents in therapy for patients with EBS.

Original languageEnglish (US)
Pages (from-to)3168-3179
Number of pages12
JournalMolecular and cellular biology
Volume24
Issue number8
DOIs
StatePublished - Apr 1 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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