T he Rel͞NF-B transcription factors have a central role in several cellular processes, including proliferation, cell adhesion, apoptosis, and regulation of the immune response (1). Under nonstimulating conditions, NF-B is retained in the cytoplasm in an inactive form because of its interaction with the inhibitory proteins I Bs. In response to an activating stimulus, I B is phosphorylated by an I B kinase (IKK) complex, which targets it for degradation by the proteasome, releasing NF-B, which translocates to the nucleus, where it regulates the transcription of target genes.Evidence gathered from studies during recent years have shown that NF-B has a growth inhibitory function in the skin. Initial studies showed that overexpression of the NF-B subunits p50 or p65 in the basal layer of the murine epidermis by using a keratin 14 (K14) promoter leads to hypoplasia of the epidermis, whereas expression of a superrepressor form of the inhibitor of NF-B type ␣ (I B␣) results in hyperplasia (2). Although K14-I B␣ mice die shortly after birth (day 7), we have shown that mice with keratin 5 (K5)-directed expression of I B␣ (K5-I B␣) to the basal layer of the epidermis survive to adulthood (3). Not only do these mice develop hyperplasia of the epidermis, but the skin phenotype of K5-I B␣ mice is also characterized by an intense neutrophil-dominated inflammation of the skin and an early development of squamous cell carcinomas (SCC).Recent data suggest that human sporadic SCC may show a block in NF-B signaling based on nuclear exclusion of the RelA NF-B subunit (ref. 4 and M.v.H., unpublished results). Furthermore, it was recently shown that coexpression of a superrepressor form of I B␣ and Ha-Ras results in neoplasia resembling invasive SCC in human keratinocytes transplanted to severe combined immunodeficient (scid͞scid) mice, supporting the relevance of a NF-B block in the induction of human SCC (4).Inflammation of the skin with neutrophil infiltration and hyperproliferation is also seen in female heterozygous Ikk␥-deficient mice, which develop a condition similar to the human X-linked disorder Incontinentia Pigmenti (IP) (5, 6). IKK␥ is the regulatory subunit of the IKK complex, which, in addition, contains the two catalytic subunits IKK␣ (IKK1) and IKK (IKK2) (1). It is now well established that human IP results from loss-of-function mutations in the IKK␥ gene (7). Interestingly, subungual keratoacanthoma-like tumors and cases of SCC have been reported as late manifestations of IP (8-11).The catalytic IKK subunit is necessary for activation of NF-B in response to proinflammatory stimuli (1). Skin-specific deletion of the IKK gene, K14-Cre͞Ikk2 FL/FL , was recently shown to result in an inflammatory phenotype with concomitant hyperproliferation of the epidermis (12), very similar to what is seen in the K5-I B␣ mice. Because the K14-Cre͞Ikk2 FL/FL mice die between day 7 and day 9 after birth, it is currently not known whether they, similar to K5-I B␣ mice, are prone to develop SCC.Besides inf lammation and hyperprolifera...
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