Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis.

Hairless (HR) is a nuclear protein with corepressor activity that is highly expressed in the skin and hair follicle. Mutations in Hairless lead to hair loss accompanied by the appearance of papules (atrichia with papular lesions), and similar phenotypes appear when the key polyamine enzymes ornithine decarboxylase (ODC) and spermidine/spermine N(1) -acetyltransferase (SSAT) are overexpressed. Both ODC and SSAT transgenic mice have elevated epidermal levels of putrescine, leading us to investigate the mechanistic link between putrescine and HR.

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

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.

Hairless and NFκB form a positive feedback loop after UVB and TNFα stimulation.

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.

RasGRP1 is essential for ras activation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in epidermal keratinocytes.

RasGRP1 is a guanine nucleotide exchange factor for Ras that binds with high affinity to diacylglycerol analogs like the phorbol esters. Recently, we demonstrated a role for RasGRP1 in skin carcinogenesis and suggested its participation in the action of tumor-promoting phorbol esters like 12-O-tetradecanoylphorbol-13-acetate (TPA) on Ras pathways in epidermal cells. Given the importance of Ras in carcinogenesis, we sought to discern whether RasGRP1 was a critical pathway in Ras activation, using a RasGRP1 knockout (KO) mouse model to examine the response of keratinocytes to TPA.

RasGRP1 transgenic mice develop cutaneous squamous cell carcinomas in response to skin wounding: potential role of granulocyte colony-stimulating factor.

Models of epidermal carcinogenesis have demonstrated that Ras is a critical molecule involved in tumor initiation and progression. Previously, we have shown that RasGRP1 increases the susceptibility of mice to skin tumorigenesis when overexpressed in the epidermis by a transgenic approach, related to its ability to activate Ras. Moreover, RasGRP1 transgenic mice develop spontaneous papillomas and cutaneous squamous cell carcinomas, some of which appear to originate in sites of injury, suggesting that RasGRP1 may be responding to signals generated during the wound-healing process.

RasGRP1 overexpression in the epidermis of transgenic mice contributes to tumor progression during multistage skin carcinogenesis.

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.