Department of Physiology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
Mol Cell Endocrinol. 2011 Oct 15;345(1-2):68-78. doi: 10.1016/j.mce.2011.07.021. Epub 2011 Jul 20.
In addition to their well-known stimulatory action, estrogens have an anti-proliferative effect. The present study was undertaken to investigate the mechanism by which 17β-estradiol (E2) inhibits insulin-like growth factor-1 (IGF-1)-induced proliferation in vitro in the rat pituitary lactotroph, a typical estrogen-responsive cell. E2 treatment of pituitary cells did not change levels of IGF-1-induced phosphorylation of proliferation-related protein kinases such as Erk1/2 and Akt. We performed global gene expression profiling by DNA microarray analysis and identified 177 genes regulated by E2 in the presence of IGF-1. These results were verified by quantitative real time PCR. The estrogen-regulated genes included several NFκB family related genes. As pharmacological inhibition of the NFκB pathway blocked IGF-1-induced lactotroph proliferation, we chose to investigate whether one NFκB pathway gene, Bcl3, was involved in the anti-proliferative action of E2. RNA interference-mediated knockdown of Bcl3 expression attenuated IGF-1-induced lactotroph proliferation. Even minimal induced overexpression of Bcl3 blocked the anti-proliferative action of E2. In contrast, Nfkb2, another E2-downregulated protein, required maximal overexpression to block the anti-proliferative action of E2. These results suggest that inhibition of Bcl3 expression is involved in the anti-proliferative action of estrogens in pituitary lactotrophs in culture.
除了它们众所周知的刺激作用外，雌激素还具有抗增殖作用。本研究旨在探讨 17β-雌二醇（E2）在体外抑制胰岛素样生长因子-1（IGF-1）诱导的大鼠垂体泌乳素细胞增殖的机制，泌乳素细胞是一种典型的雌激素反应细胞。E2 处理垂体细胞不会改变 IGF-1 诱导的增殖相关蛋白激酶（如 Erk1/2 和 Akt）磷酸化水平。我们通过 DNA 微阵列分析进行了全基因表达谱分析，并在 IGF-1 存在的情况下鉴定出 177 个受 E2 调节的基因。这些结果通过定量实时 PCR 得到验证。受雌激素调节的基因包括几个 NFκB 家族相关基因。由于 NFκB 途径的药理学抑制阻断了 IGF-1 诱导的泌乳素细胞增殖，因此我们选择研究 NFκB 途径基因 Bcl3 是否参与 E2 的抗增殖作用。RNA 干扰介导的 Bcl3 表达敲低减弱了 IGF-1 诱导的泌乳素细胞增殖。即使 Bcl3 的最小诱导过表达也阻止了 E2 的抗增殖作用。相比之下，另一种 E2 下调蛋白 Nfkb2 需要最大过表达才能阻断 E2 的抗增殖作用。这些结果表明，抑制 Bcl3 表达参与了雌激素在培养中的垂体泌乳素细胞中的抗增殖作用。
