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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 NF?B and its downstream effectors. We show that in the epidermis, Hr is an early UVB response gene that regulates NF?B activation and thereby controls cellular responses to irradiation. Therefore, when Hr expression is decreased in Hr mutant animals there is a corresponding increase in NF?B activity that is augmented by UVB irradiation. This constitutive activation of NF?B 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.

SUBMITTER: Kim H 

PROVIDER: S-EPMC3382590 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Loss of hairless confers susceptibility to UVB-induced tumorigenesis via disruption of NF-kappaB signaling.

Kim Hyunmi H   Casta Alexandre A   Tang Xiuwei X   Luke Courtney T CT   Kim Arianna L AL   Bickers David R DR   Athar Mohammad M   Christiano Angela M AM  

PloS one 20120625 6


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  ...[more]

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