Curtis S W, Washburn T, Sewall C, DiAugustine R, Lindzey J, Couse J F, Korach K S
Receptor Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12626-30. doi: 10.1073/pnas.93.22.12626.
Past studies have shown that epidermal growth factor (EGF) is able to mimic the uterotropic effects of estrogen in the rodent. These studies have suggested a "cross-talk" model in which EGF receptor (EGF-R) signaling results in activation of nuclear estrogen receptor (ER) and its target genes in an estrogen-independent manner. Furthermore, in vitro studies have indicated the requirement for ER in this mechanism. To verify the requirement for ER in an in vivo system, EGF effects were studied in the uteri of ER knockout (ERKO) mice, which lack functional ER. The EGF-R levels, autophosphorylation, and c-fos induction were observed at equivalent levels in both genotypes indicating that removal of ER did not disrupt the EGF responses. Induction of DNA synthesis and the progesterone receptor gene in the uterus were measured after EGF treatment of both ERKO and wild-type animals. Wild-type mice showed increases of 4.3-fold in DNA synthesis, as well as an increase in PR mRNA after EGF treatment. However, these responses were absent in ERKO mice, confirming that the estrogen-like effects of EGF in the mouse uterus do indeed require the ER. These data conclusively demonstrate the coupling of EGF and ER signaling pathways in the rodent reproductive tract.
过去的研究表明，表皮生长因子（EGF）能够模拟雌激素对啮齿动物子宫的促生长作用。这些研究提出了一种“串扰”模型，即表皮生长因子受体（EGF-R）信号传导导致核雌激素受体（ER）及其靶基因以非雌激素依赖的方式激活。此外，体外研究表明该机制需要ER的参与。为了在体内系统中验证ER的必要性，对缺乏功能性ER的雌激素受体基因敲除（ERKO）小鼠子宫中的EGF作用进行了研究。两种基因型小鼠的EGF-R水平、自身磷酸化以及c-fos诱导水平相当，这表明去除ER不会破坏EGF反应。在用EGF处理ERKO和野生型动物后，检测了子宫中DNA合成及孕激素受体基因的诱导情况。野生型小鼠在EGF处理后DNA合成增加了4.3倍，PR mRNA也有所增加。然而，这些反应在ERKO小鼠中未出现，证实了EGF在小鼠子宫中的雌激素样作用确实需要ER。这些数据确凿地证明了啮齿动物生殖道中EGF和ER信号通路的耦合。
