title: Loss of hairless confers susceptibility to UVB-induced tumorigenesis via disruption of NF-kappaB signaling.
abstract: In order to model squamous cell carcinoma development in vivo, researchers have long preferred hairless mouse models such as SKH-1 mice that have traditionally been classified as 'wild-type' mice irrespective of the genetic factors underlying their hairless phenotype. The work presented here shows that mutations in the Hairless (Hr) gene not only result in the hairless phenotype of the SKH-1 and Hr(-/-) mouse lines but also cause aberrant activation of NFκB and its downstream effectors. We show that in the epidermis, Hr is an early UVB response gene that regulates NFκB activation and thereby controls cellular responses to irradiation. Therefore, when Hr expression is decreased in Hr mutant animals there is a corresponding increase in NFκB activity that is augmented by UVB irradiation. This constitutive activation of NFκB in the Hr mutant epidermis leads to the stimulation a large variety of downstream effectors including the cell cycle regulators cyclin D1 and cyclin E, the anti-apoptosis protein Bcl-2, and the pro-inflammatory protein Cox-2. Therefore, Hr loss results in a state of uncontrolled epidermal proliferation that promotes tumor development, and Hr mutant mice should no longer be considered merely hairless 'wild-type' mice. Instead, Hr is a crucial UVB response gene and its loss creates a permissive environment that potentiates increased tumorigenesis.
authors: Department of Genetics & Development, Columbia University, College of Physicians & Surgeons, New York, New York, United States of America.
authors: Hyunmi
authors: H
authors: Kim
authors: Alexandre
authors: A
authors: Casta
authors: Xiuwei
authors: X
authors: Tang
authors: Courtney T
authors: CT
authors: Luke
authors: Arianna L
authors: AL
authors: Kim
authors: David R
authors: DR
authors: Bickers
authors: Mohammad
authors: M
authors: Athar
authors: Angela M
authors: AM
authors: Christiano
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D014157:Transcription Factors; C088661:hr protein, mouse