Abstract
Gene knockout studies unexpectedly reveal a pivotal role for IκB kinase alpha (IKKα) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikkα 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. IKKα deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikkα floxed mice. On the other hand, transgenic mice overexpressing IKKα 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 IKKα represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKα deletion mediated by a mutation, which generates a stop codon in the Ikkα gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKα and Ikkα mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKα 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.
Highlights
I B kinase alpha (IKK ), known as CHUK, is an 85-kD polypeptide with 745 amino acids. It consists of a putative kinase catalytic domain (KD, aa 15–300) containing 12 regions of homology that are characteristic of a protein serine kinase, a leucine zipper (LZ) motif, and a helix-loop-helix (HLH) motif, and it belongs to a classic zipper protein family, which includes c-myc, Id1, C/EBP, and Jun [1,2]
These results demonstrate that Ikk is haploid insufficient for suppressing tumor progression, that somatic IKK deletion can facilitate skin carcinoma development, and that the tumor progression may be related to a de-differentiation program in keratinocytes
Lori.IKK inhibits ultraviolet B light (UVB)-induced skin carcinogenesis. These results demonstrate that IKK is important for suppressing UVB-induced skin carcinogenesis
Summary
I B kinase alpha (IKK ), known as CHUK, is an 85-kD polypeptide with 745 amino acids (aa). It consists of a putative kinase catalytic domain (KD, aa 15–300) containing 12 regions of homology that are characteristic of a protein serine kinase, a leucine zipper (LZ) motif, and a helix-loop-helix (HLH) motif, and it belongs to a classic zipper protein family, which includes c-myc, Id1, C/EBP, and Jun [1,2]. IKK can form homodimers and heterodimers, which lead to distinct pathways in a cell-specific manner in vivo [3,4]. We discuss how different mouse models illustrate the physiological functions of IKK in the skin
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