Role of β-TrCP ubiquitin ligase receptor in UVB mediated responses in skin

Skin cancers are the most common cancers in the United States. Exposure to UVB radiation is a major risk factor for skin cancer induction. SCFβ-TrCP E3 ubiquitin ligase has been found to be involved in cell cycle, cell proliferation and transformation. Aberrant up-regulation of beta-transducin repeats-containing proteins (β-TrCP) is often found in cancer cell lines and primary tumors. We have previously demonstrated that β-TrCP2 is over-expressed in chemically induced mouse skin tumors [1]. Various cellular stress stimuli, including UVB, induce an increase in β-TrCP1 mRNA and protein levels in human cells [2]. We have previously shown that inhibition of β-TrCP function, by induction of dominant negative β-TrCP2 (β-TrCP2ΔF), in vitro in hTERT immortalized normal keratinocytes, results in increase in UVB induced apoptosis [3]. We have generated transgenic mice with inducible, selective expression of dominant negative β-TrCP2 in epidermis with the Keratin 5 promoter (K5-rTA × TRE-HA-β-TrCPΔF). Here we report that inhibition of β-TrCP function in mouse epidermis results in decrease in UVB-induced edema, hyperplasia, and inflammatory response and increment in UVB-induced apoptosis in skin. Our results suggest that β-TrCP may be an essential player in UVB induced responses in skin and can be a potential therapeutic target for skin cancer.

Research highlights► We have generated K5-rTA × TRE-HA-β-TrCPΔF transgenic mice with tetracycline responsive, selective expression of dominant negative β-TrCP2 (β-TrCP2ΔF) in epidermis with the Keratin 5 promoter. ► Inhibition of β-TrCP function, by expression of β-TrCP2ΔF on mouse epidermis results in decrease in UVB-induced inflammatory response and increment in UVB-induced apoptosis in skin. ► UVB induced Interleukin 6 (IL-6) secretion is diminished by β-TrCPΔF expression. ► Decline in UVB-induced pathological changes as skin edema and hyperplasia are also pertinent in transgenic mice with induced expression of β-TrCP2ΔF. ► Inhibition of β-TrCP function results in reduction of UVB induced ODC (Ornithine decarboxylase) enzyme activity in mouse skin.