ALTERATIONS IN NF-KAPPA-B FUNCTION IN TRANSGENIC EPITHELIAL TISSUE DEMONSTRATE A GROWTH-INHIBITORY ROLE FOR NF-KAPPA-B

Stratified epithelium contains a mitotically active basal layer of cel ls that cease proliferating, then migrate outwards and undergo termina l differentiation. The control of this process, which is abnormal in c utaneous neoplasia and inflammation, is not well understood. In normal epidermis, NF-kappa B proteins were found to exist in the cytoplasm o f basal cells and then to localize in the nuclei of suprabasal cells, suggesting a role for NF-kappa B in the switch from proliferation to g rowth arrest and differentiation. Functional blockade of NF-kappa B by expressing dominant-negative NF-kappa B inhibitory proteins in transg enic murine and human epidermis produced hyperplastic epithelium in vi vo. Consistent with this, application of a pharmacologic inhibitor of NF-kappa B to intact skin induced epidermal hyperplasia. In contrast, overexpression of active p50 and p65 NF-kappa B subunits in transgenic epithelium produced hypoplasia and growth inhibition. These data sugg est that spatially restricted NF-kappa B activation occurs in stratifi ed epithelium and indicate that NF-kappa B activation in this tissue, in contrast to its role in other settings, is important for cellular g rowth inhibition.