title: Hairless and NFκB form a positive feedback loop after UVB and TNFα stimulation.
abstract: Hairless (HR) is a nuclear protein with corepressor activity whose exact function in the skin remains to be determined. Mutations in both human and mouse Hairless lead to hair loss accompanied by the appearance of papules, a disorder called atrichia with papular lesions. Furthermore, mice with mutations in HR are known to have a higher susceptibility to ultraviolet radiation-induced tumorigenesis, suggesting that HR plays a crucial role in the epidermal UVB response. Using normal human keratinocytes (NHKs) and keratinocytes containing a mutation in HR, we found that HR is an early UVB response gene that negatively regulates NFκB mRNA expression. HR mutant keratinocytes have a dysregulated UVB response that includes increased proliferation and the aberrant activation of NFκB effector genes. Additionally, we show that another UVB response gene, TNFα, negatively regulates HR mRNA expression. TNFα-induced negative regulation of HR occurs through a direct interaction of the p65 subunit with a single NFκB-binding domain located in the HR promoter region. Therefore, we show for the first time that HR and NFκB participate in a positive feedback loop that can be initiated either by UVB or TNFα.
authors.affiliation: Department of Dermatology, Columbia University, New York, NY, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Casta
authors.forename: Hyunmi
authors.initials: H
authors.lastname: Kim
authors.forename: Courtney T
authors.initials: CT
authors.lastname: Luke
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bachelor
authors.forename: Andrew
authors.initials: A
authors.lastname: Engelhard
authors.forename: David M
authors.initials: DM
authors.lastname: Owens
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
mesh_terms: D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D025461:Feedback, Physiological / Q000187:drug effects / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014466:Ultraviolet Rays
chemical_list: C490267:HR protein, human; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha