Ignar-Trowbridge D M, Pimentel M, Teng C T, Korach K S, McLachlan J A
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Environ Health Perspect. 1995 Oct;103 Suppl 7(Suppl 7):35-8. doi: 10.1289/ehp.95103s735.
Epidermal growth factor reproduces many of the effects of estrogen on the murine female reproductive tract and may partially mediate estrogen-induced growth and differentiation. The mechanism by which the actions of estrogens and epidermal growth factor (EGF) converge is unknown. The studies described herein were performed to investigate the possibility that some of the actions of EGF may be mediated through the estrogen receptor. A specific estrogen receptor (ER) antagonist inhibited estrogenlike effects of EGF in the mouse uterus, specifically induction of DNA synthesis and phosphatidylinositol turnover. In addition, EGF elicited enhanced nuclear localization of uterine ER and formation of a unique nuclear form of ER that is present after estrogen treatment. These in vivo observations indicated that EGF may elicit some of its actions by activation of nuclear ER. Thus, the effect of peptide growth factors on activation of a consensus estrogen response element was assessed in Ishikawa human endometrial adenocarcinoma cells, which contain negligible ER levels, and in BG-1 human ovarian adenocarcinoma cells, which contain abundant ER. EGF and TGF alpha induced transcriptional activation of a consensus estrogen response element (ERE) in an ER-dependent manner in both cell types. In addition, insulinlike growth factor I (IGF-I) was as potent as 17 beta-estradiol in BG-1 cells. Synergism between growth factors and estrogen was observed in both cell types, although synergism was not observed between the different classes of growth factors [i.e., transforming growth factor alpha (TGF alpha) and IGF-I] in BG-1 cells. The most potent activator of ERE-dependent transcription was a protein kinase C activator (TPA), which acted synergistically with 17 beta-estradiol. A protein kinase C inhibitor abolished the effect of TPA but not that of 17 beta-estradiol, IGF-I, or TGF alpha. A protein kinase A activator elicited ER-dependent activation of transcription and did not synergize with estrogen or growth factors. In conclusion, some physiologic actions of peptide growth factors are dependent on ER. Indeed, growth factors are capable of eliciting ER-dependent activation of an ERE. Both the protein kinase A and protein kinase C pathways can elicit ER-dependent transcriptional activation; however, it is unlikely that these pathways mediate the effects of peptide growth factors on the ER in BG-1 cells.
表皮生长因子可重现雌激素对小鼠雌性生殖道的许多作用，并可能部分介导雌激素诱导的生长和分化。雌激素和表皮生长因子（EGF）作用趋同的机制尚不清楚。本文所述研究旨在探讨EGF的某些作用可能通过雌激素受体介导的可能性。一种特异性雌激素受体（ER）拮抗剂可抑制EGF在小鼠子宫中的雌激素样作用，特别是对DNA合成和磷脂酰肌醇代谢的诱导作用。此外，EGF可使子宫ER的核定位增强，并形成雌激素处理后出现的一种独特的核形式的ER。这些体内观察结果表明，EGF可能通过激活核ER发挥其部分作用。因此，在ER水平可忽略不计的石川人子宫内膜腺癌细胞和ER含量丰富的BG-1人卵巢腺癌细胞中，评估了肽生长因子对共有雌激素反应元件激活的影响。在这两种细胞类型中，EGF和转化生长因子α（TGFα）均以ER依赖的方式诱导共有雌激素反应元件（ERE）的转录激活。此外，在BG-1细胞中，胰岛素样生长因子I（IGF-I）与17β-雌二醇的作用相当。在这两种细胞类型中均观察到生长因子与雌激素之间的协同作用，尽管在BG-1细胞中不同类别的生长因子[即转化生长因子α（TGFα）和IGF-I]之间未观察到协同作用。最有效的ERE依赖转录激活剂是蛋白激酶C激活剂（TPA），它与17β-雌二醇协同作用。蛋白激酶C抑制剂可消除TPA的作用，但不能消除17β-雌二醇、IGF-I或TGFα的作用。蛋白激酶A激活剂可引发ER依赖的转录激活，且不与雌激素或生长因子协同作用。总之，肽生长因子的某些生理作用依赖于ER。事实上，生长因子能够引发ER依赖的ERE激活。蛋白激酶A和蛋白激酶C途径均可引发ER依赖的转录激活；然而，这些途径不太可能介导肽生长因子对BG-1细胞中ER的作用。
