Nuclear factor kappa B subunits induce epithelial cell growth arrest

Nuclear factor kappa B (NF-kappa B) gene-regulatory proteins play important roles in inflammation, neoplasia, and programmed cell death. Recently, blo ckade of NF-kappa B function has been shown to result in epithelial hyperpl asia, suggesting a potential role for NF-kappa B in negative growth regulat ion. We expressed active NF-kappa B subunits in normal epithelial cells and found that NF-kappa B profoundly inhibits cell cycle progression. This gro wth inhibition is resistant to mitogenic stimuli and is accompanied by othe r features of irreversible growth arrest. NF-kappa B-triggered cell cycle a rrest is also associated with selective induction of the cyclin-dependent k inase inhibitor p21(Cip1), with overexpression of p21(Cip1) alone inducing findings similar to those seen with NF-kappa B in vitro. An active NF-kappa B subunit expressed in the epidermis of p21(Cip1-/-) mice, however, displa ys only partial growth-inhibitory effects, suggesting that full NF-kappa B growth inhibition is only partially p21(Cip1) dependent in this setting. Th ese data indicate that NF-kappa B can trigger cell cycle arrest in epitheli al cells in association with selective induction of a cell cycle inhibitor.