Mouse Genetic Models Reveal Surprising Functions of IkB Kinase Alpha in Skin Development and Skin Carcinogenesis

Abstract: Gene knockout studies unexpectedly reveal a pivotal role for IkB kinase alpha (IKKa) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikka heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKa deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikka floxed mice. On the other hand, transgenic mice overexpressing IKKa in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKa represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKa deletion mediated by a mutation, which generates a stop codon in the Ikka gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKa and Ikka mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKa in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside.