Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB
Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB
复制标题
DOI：
10.1073/pnas.95.5.2307
复制
发表时间：
1998-03-03
影响因子：
11.1
通讯作者：
Khavari, PA
中科院分区：
文献类型：
--
作者：
Seitz, CS;Lin, Q;Khavari, PA
复层上皮包含一个有丝分裂活跃的基底层细胞，这些细胞停止增殖，然后向外迁移并经历终末分化。在皮肤肿瘤形成和炎症中此过程异常，其调控机制尚未完全清楚。在正常表皮中，发现NF - κB蛋白存在于基底细胞的细胞质中，然后定位于基底上层细胞的细胞核，这表明NF - κB在从增殖到生长停滞和分化的转换中起作用。通过在转基因小鼠和人表皮中表达显性负性NF - κB抑制蛋白对NF - κB进行功能性阻断，在体内产生了增生性上皮。与此一致的是，将一种NF - κB的药理抑制剂应用于完整皮肤可诱导表皮增生。相反，在转基因上皮中过表达活性p50和p65 NF - κB亚单位会导致发育不全和生长抑制。这些数据表明在复层上皮中存在空间受限的NF - κB激活，并且表明与在其他情况下的作用相反，该组织中NF - κB的激活对细胞生长抑制很重要。
Stratified epithelium contains a mitotically active basal layer of cells that cease proliferating, then migrate outwards and undergo terminal differentiation. The control of this process, which is abnormal in cutaneous neoplasia and inflammation, is not well understood. In normal epidermis, NF-kappa B proteins were found to exist in the cytoplasm of 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 growth arrest and differentiation. Functional blockade of NF-kappa B by expressing dominant-negative NF-kappa B inhibitory proteins in transgenic murine and human epidermis produced hyperplastic epithelium in vivo. 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 suggest that spatially restricted NF-kappa B activation occurs in stratified epithelium and indicate that NF-kappa B activation in this tissue, in contrast to its role in other settings, is important for cellular growth inhibition.