Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB

Abstract

Stratified epithelium contains a mitotically active basal layer of cells that cease proliferating, then migrate outwards and undergo terminal differentiation. The control of this process, which is abnormal in cutaneous neoplasia and inf lammation, is not well understood. In normal epidermis, NF-B proteins were found to exist in the cytoplasm of basal cells and then to localize in the nuclei of suprabasal cells, suggesting a role for NF-B in the switch from proliferation to growth arrest and differentiation. Functional blockade of NF-B by expressing dominant-negative NF-B inhibitory proteins in transgenic murine and human epidermis produced hyperplastic epithelium in vivo. Consistent with this, application of a pharmacologic inhibitor of NF-B to intact skin induced epidermal hyperplasia. In contrast, overexpression of active p50 and p65 NF-B subunits in transgenic epithelium produced hypoplasia and growth inhibition. These data suggest that spatially restricted NF-B activation occurs in stratified epithelium and indicate that NF-B activation in this tissue, in contrast to its role in other settings, is important for cellular growth inhibition.

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

“…This could be explained by the higher NF-kB activity found in the C57-CYLD C/S cells, in line with the findings indicating that malignant epidermal cells have accumulated molecular alterations that enable a 'switch' of NFkB function from being a tumor suppressor in normal murine and human keratinocytes (Seitz et al, 1998;van Hogerlinden et al, 1999;Dajee et al, 2003) to being a tumor promoter (Ren et al, 2006). Tumor epidermal cells expressing CYLD C/S also show an important increase in the nuclear localization of Bcl3, p52 and b-catenin.…”

Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts

“…The observation that NF-kB proteins are cytoplasmic in mitotically active basal cells but localize to the nucleus of di erentiated supradermal cells suggested that NF-kB may be involved in the switch from proliferation to growth arrest and di erentiation. Consistent with such as model, targeted expression of IkBa m to the epidermis of transgenic mice leads to epithelial hyperplasia (Setiz et al, 1998), while expression of transgenes for constitutively nuclear p50 or RelA mutants leads to an inhibition of epithelial cell growth (Seitz et al, 1998). These ®ndings are consistent with the recent observation that IKKa-de®cient mice, which fail to activate Rel/NF-kB in epithelial cells also exhibit a block in epithelial cell di erentiation coupled with basal cell hyper-proliferation (Hu et al, 1999;Takeda et al, 1999).…”

“…Alternatively and certainly possible, the IKK complex, especially IKKa, phosphorylates substrates other than IkB or regulates additional signaling pathways. Nevertheless, evidence of a role for Rel/NF-kB factors in vertebrate limb and skin development has previously come from over-expressing mutant IkBa in chick embryos (Bushdid et al, 1998;Kanegae et al, 1998) and in the dermis of transgenic mice (Seitz et al, 1998). The normal induction of Rel/NF-kB in ikba 7/7 embryonic ®broblasts in response to the pro-inflammatory cytokines TNFa or IL-1 occurs via IKKb (Hu et al, 1999;Takeda et al, 1999), and this ®nding suggests that an unknown set of signals operating through IKKa is required for the induction of Rel/NFkB during skin and skeletal development.…”

Current insights into the regulation of programmed cell death by NF-κB

“…Although NF-kB is generally implicated in cancer by virtue of its ability to drive cell proliferation and survival, the inhibition of NF-kB in epidermal cells is associated with increased proliferation and hyperplasia (Seitz et al, 1998;van Hogerlinden et al, 1999;Seitz et al, 2000). Furthermore, inhibition of NF-kB activity combined with expression of oncogenic Ras in epidermal keratinocytes leads to invasive neoplasia with features similar to those of squamous cell carcinoma (Dajee et al, 2003).…”