Critical role of IkappaB kinase alpha in embryonic skin development and skin carcinogenesis

Abstract

IkappaB kinase alpha (IKKalpha), IKKbeta, and IKKgamma/NEMO form the IKK complex, which is essential for NF-kappaB activation. However, genetic studies have shown that the role of IKKalpha is distinct from that of IKKbeta or IKKgamma in the development of the mouse embryonic skin. Loss of IKKalpha has been shown to cause epidermal hyperplasia, prevent keratinocyte terminal differentiation, and impair the formation of the skin, resulting in the deaths of IKKalpha-deficient (Ikkalpha-/-) mice soon after birth. Recent experimental data from several laboratories have revealed that IKKalpha functions as a tumor suppressor in human squamous cell carcinomas (SCCs) of skin, lungs, and head and neck. Chemical carcinogenesis studies using mice have shown that reduction in IKKalpha expression increases the number and size of Ras-initiated skin tumors and promotes their progression, indicating that reduced IKKalpha expression provides a selective growth advantage that cooperates with Ras activity to promote skin carcinogenesis. In this review, we will summarize these findings from our and other studies on the role that IKKalpha plays in development of the mouse embryonic skin and skin carcinogenesis.

Fig. 1.

IKKα loss induces epidermal hyperplasia, prevents terminal differentiation, and impairs the formation of the skin. Two arrows indicate the epidermis of the skin. The hematoxylin and eosin-stained paraffin sections were obtained from newborn mice with an FVB background. Original magnifications, x 200

Fig. 2.

Reduction of 14–3-30 and NPM protein levels in skin carcinomas. a. 14–3-3σ and NPM levels in papillomas and carcinomas, detected by Western blotting. +/+ and +/−, Ikkα^+/− and Ikkα^+/+ ß-Actin, a protein loading control; Ratio, densities of the IKKα signal normalized to those of the ß-Actin signal (ratio for wild-type skin was set as 1 ). Signals were scanned by a Kodak Image Station 440 with the 103.6 software program (Kodak) and analyzed by the lmageQuant TL software program (version 2003.02). b and c. Comparison of relative 14–3-3σ and NPM levels in papillomas (pap) and carcinomas (car).