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Hairless and NFκB Form a Positive Feedback Loop After UVB and TNFα Stimulation †
Author(s) -
Casta Alexandre,
Kim Hyunmi,
Luke Courtney T.,
Bachelor Michael A.,
Engelhard Andrew,
Owens David M.,
Christiano Angela M.
Publication year - 2012
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1111/j.1751-1097.2012.01110.x
Subject(s) - hairless , corepressor , epidermis (zoology) , effector , biology , mutant , carcinogenesis , keratinocyte , nf κb , nfkb1 , tumor necrosis factor alpha , microbiology and biotechnology , mutation , cancer research , gene expression , gene , signal transduction , endocrinology , genetics , cell culture , repressor , transcription factor , anatomy
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.