Nuclear factor kappaB subunits induce epithelial cell growth arrest.
Nuclear factor kappaB (NF-kappaB) gene-regulatory proteins play important roles in inflammation, neoplasia, and programmed cell death. Recently, blockade of NF-kappaB function has been shown to result in epithelial hyperplasia, suggesting a potential role for NF-kappaB in negative growth regulation. We expressed active NF-kappaB subunits in normal epithelial cells and found that NF-kappaB profoundly inhibits cell cycle progression. This growth inhibition is resistant to mitogenic stimuli and is accompanied by other features of irreversible growth arrest. NF-kappaB-triggered cell cycle arrest is also associated with selective induction of the cyclin-dependent kinase inhibitor p21CiP1, with overexpression of p21(Cip1) alone inducing findings similar to those seen with NF-kappaB in vitro. An active NF-kappaB subunit expressed in the epidermis of p21(CiP1-/- mice, however, displays only partial growth-inhibitory effects, suggesting that full NF-kappaB growth inhibition is only partially p21(Cip1) dependent in this setting. These data indicate that NF-kappaB can trigger cell cycle arrest in epithelial cells in association with selective induction of a cell cycle inhibitor.
Seitz
C S
CS
VA Palo Alto Health Care System and the Program in Epithelial Biology, Stanford University School of Medicine, California 94305, USA.
Deng
H
H
Hinata
K
K
Lin
Q
Q
Khavari
P A
PA
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000473:pathology
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; D016328:NF-kappa B