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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.

RasGRP1 is a guanine nucleotide exchange factor for Ras, activated in response to the second messenger diacylglycerol and its ultrapotent analogues, the phorbol esters. We have previously shown that RasGRP1 is expressed in mouse epidermal keratinocytes and that transgenic mice overexpressing RasGRP1 in the epidermis under the keratin 5 promoter (K5.RasGRP1) are prone to developing spontaneous papillomas and squamous cell carcinomas, suggesting a role for RasGRP1 in skin tumorigenesis. Here, we examined the response of the K5.RasGRP1 mice to multistage skin carcinogenesis, using 7,12-dimethylbenz(a)anthracene as carcinogen and 12-O-tetradecanoylphorbol-13-acetate (TPA) as tumor promoter. We found that whereas tumor multiplicity did not differ between transgenic and wild-type groups, the transgenic tumors were significantly larger than those observed in the wild-type mice (wild-type, 4.58 F 0.25 mm; transgenic, 9.83 F 1.05 mm). Histologic analysis further revealed that squamous cell carcinomas generated in the transgenic mice were less differentiated and more invasive than the wild-type tumors. Additionally, 30% of the transgenic mice developed tumors in the absence of initiation, suggesting that RasGRP1 overexpression could partially substitute for the initiation step induced by dimethylbenz(a)anthracene. In primary keratinocytes isolated from K5.RasGRP1 mice, TPA stimulation induced higher levels of Ras activation compared with the levels measured in the wild-type cells, indicating that constitutive overexpression of RasGRP1 in epidermal cells leads to elevated biochemical activation of endogenous Ras in response to TPA. The present data suggests that RasGRP1 participates in skin carcinogenesis via biochemical activation of endogenous wild-type Ras and predisposes to malignant progression in cooperation with Ras oncogenic signals.