Seitz C S, Deng H, Hinata K, Lin Q, Khavari P A
VA Palo Alto Health Care System and the Program in Epithelial Biology, Stanford University School of Medicine, California 94305, USA.
Cancer Res. 2000 Aug 1;60(15):4085-92.
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.
核因子κB（NF-κB）基因调控蛋白在炎症、肿瘤形成和程序性细胞死亡中发挥重要作用。最近，研究表明阻断NF-κB功能会导致上皮细胞增生，这提示NF-κB在负性生长调节中可能发挥作用。我们在正常上皮细胞中表达活性NF-κB亚基，发现NF-κB能显著抑制细胞周期进程。这种生长抑制对促有丝分裂刺激具有抗性，并伴有不可逆生长停滞的其他特征。NF-κB引发的细胞周期停滞还与细胞周期蛋白依赖性激酶抑制剂p21CiP1的选择性诱导有关，单独过表达p21（Cip1）在体外诱导出的结果与NF-κB相似。然而，在p21（CiP1-/-）小鼠表皮中表达的活性NF-κB亚基仅表现出部分生长抑制作用，这表明在这种情况下，NF-κB的完全生长抑制仅部分依赖于p21（Cip1）。这些数据表明，NF-κB可通过选择性诱导细胞周期抑制剂触发上皮细胞的细胞周期停滞。
