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Nuclear factor kappaB subunits induce epithelial cell growth arrest
1VA Palo Alto Health Care System and the Program in Epithelial Biology, Stanford University School of Medicine, California 94305, USA.
Abstract:
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.
Insights
Nuclear factor kappaB (NF-kappaB) profoundly inhibits epithelial cell cycle progression, acting as a negative growth regulator. This arrest is linked to p21CiP1 induction but is not fully dependent on it.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Nuclear factor kappaB (NF-kappaB) proteins regulate key cellular processes including inflammation, neoplasia, and apoptosis.
- Recent studies suggest NF-kappaB's involvement in negative growth regulation, as its blockade leads to epithelial hyperplasia.
Purpose of the Study:
- To investigate the role of active NF-kappaB subunits in regulating epithelial cell cycle progression.
- To determine the mechanism underlying NF-kappaB-mediated growth inhibition.
Main Methods:
- Expression of active NF-kappaB subunits in normal epithelial cells.
- Assessment of cell cycle progression and growth arrest.
- Analysis of cyclin-dependent kinase inhibitor p21CiP1 expression.
- Experiments in p21(CiP1-/-) mice.
Main Results:
- NF-kappaB profoundly inhibits epithelial cell cycle progression, inducing irreversible growth arrest resistant to mitogenic stimuli.
- NF-kappaB triggers cell cycle arrest through the selective induction of the cyclin-dependent kinase inhibitor p21CiP1.
- While p21CiP1 is crucial, full NF-kappaB-mediated growth inhibition in the epidermis is only partially dependent on p21CiP1.
Conclusions:
- NF-kappaB acts as a potent inhibitor of epithelial cell cycle progression.
- The induction of p21CiP1 is a key mechanism by which NF-kappaB enforces cell cycle arrest.
- NF-kappaB's growth-inhibitory function involves pathways beyond p21CiP1.