AP-2alpha: a regulator of EGF receptor signaling and proliferation in skin epidermis.
AP-2alpha: a regulator of EGF receptor signaling and proliferation in skin epidermis.
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DOI：
10.1083/jcb.200510002
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发表时间：
2006-01-30
期刊：
影响因子：
--
通讯作者：
Fuchs E
中科院分区：
文献类型：
--
作者：
Wang X;Bolotin D;Chu DH;Polak L;Williams T;Fuchs E
AP-2转录因子与表皮生物学有关，但其功能意义尚不清楚。利用条件性基因敲除技术，我们证明了AP-2α对于调节表皮生长和分化之间的平衡是必不可少的。在体内，缺乏AP-2α的表皮在分化层中表现出表皮生长因子受体的高表达，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表明，表皮生长因子受体是AP-2α抑制的直接靶基因，在AP-2α缺失的情况下，这主要表现为依赖于表皮生长因子的磷酸肌醇-3激酶/AKT的过度活性。综上所述，我们的发现揭示了AP-2α在细胞退出基底层并退出细胞周期时在调控EGFR基因转录方面迄今尚未被认识到的抑制作用。这些结果揭示了为什么AP-2α水平升高通常与终末分化有关，以及为什么肿瘤细胞通常表现为AP-2α降低和EGFR蛋白升高。
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-2α is essential for governing the balance between growth and differentiation in epidermis. In vivo, epidermis lacking AP-2α 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-2α repression, and, in the absence of AP-2α, this is manifested primarily in excessive EGF-dependent phosphoinositol-3 kinase/Akt activity. Together, our findings unveil a hitherto unrecognized repressive role for AP-2α 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-2α levels are often associated with terminal differentiation and why tumor cells often display reduced AP-2α and elevated EGFR proteins.
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