Wang Xuan, Bolotin Diana, Chu David H, Polak Lisa, Williams Trevor, Fuchs Elaine
The Howard Hughes Medical Institute, Rockefeller University, New York, NY 10021, USA.
J Cell Biol. 2006 Jan 30;172(3):409-21. doi: 10.1083/jcb.200510002.
AP-2 transcription factors have been implicated in epidermal biology, but their functional significance has remained elusive. Using conditional knockout technology, we show that AP-2alpha is essential for governing the balance between growth and differentiation in epidermis. In vivo, epidermis lacking AP-2alpha exhibits elevated expression of the epidermal growth factor receptor (EGFR) in the differentiating layers, resulting in hyperproliferation when the receptors are activated. Chromatin immunoprecipitation and promoter activity assays identify EGFR as a direct target gene for AP-2alpha repression, and, in the absence of AP-2alpha, this is manifested primarily in excessive EGF-dependent phosphoinositol-3 kinase/Akt activity. Together, our findings unveil a hitherto unrecognized repressive role for AP-2alpha in governing EGFR gene transcription as cells exit the basal layer and withdraw from the cell cycle. These results provide insights into why elevated AP-2alpha levels are often associated with terminal differentiation and why tumor cells often display reduced AP-2alpha and elevated EGFR proteins.
AP-2转录因子与表皮生物学有关，但其功能意义仍不清楚。利用条件性基因敲除技术，我们发现AP-2α对于控制表皮生长和分化之间的平衡至关重要。在体内，缺乏AP-2α的表皮在分化层中表皮生长因子受体（EGFR）表达升高，当受体被激活时导致过度增殖。染色质免疫沉淀和启动子活性分析确定EGFR是AP-2α抑制的直接靶基因，并且在没有AP-2α的情况下，这主要表现为过度的表皮生长因子依赖性磷酸肌醇-3激酶/蛋白激酶B活性。总之，我们的研究结果揭示了AP-2α在细胞退出基底层并退出细胞周期时对EGFR基因转录具有迄今未被认识的抑制作用。这些结果为为什么AP-2α水平升高常与终末分化相关以及为什么肿瘤细胞常显示AP-2α降低和EGFR蛋白升高提供了见解。
