5月9日，Yeshiva大学爱因斯坦医学院的研究人员已经发现一种能抑制雌激素作用的分子。雌性激素的增长，对生长、生殖组织的修复和子宫内膜癌和乳腺癌的发展起着关键作用。动物实验中发现，这一分子研究发现可能会带来用于预防和治疗人类的雌激素有关的疾病的新疗法。研究结果发表在PNAS杂志上。
激素雌二醇（雌激素的最重要的形式）和孕激素是为怀孕子宫服务的。他们引发了一系列的细胞增殖和细胞分化事件，为受精卵植入子宫内膜（子宫内膜）提供良好环境。虽然这个过程中受到严格控制，但有时子宫细胞会异常增生，导致月经紊乱、子宫内膜息肉、子宫内膜异位症或子宫内膜癌等，子宫内膜癌是最常见的女性生殖道恶性肿瘤。
Jeffrey Pollard,博士说：这些疾病背后的分子机制仍是个谜，同时激素调节的子宫内膜正常细胞的增殖的机制也不明确。
啮齿动物研究中， Pollard博士发现， KLF15（Kruppel样转录因子-15）控制雌二醇和孕激素在子宫内膜抑制MCM2的生成，MCM2参与DNA的合成过程。
Pollard博士说：我们的研究结果可能为预防或治疗子宫内膜癌和乳腺癌提供可能性，通过促进KLF15能治疗雌激素有关的癌症和其他疾病。（生物谷：Bioon.com）
doi:10.1073/pnas.1118515109
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KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing
Sanhita Ray and Jeffrey W. Pollard1
In the epithelial compartment of the uterus, estradiol-17β (E2) induces cell proliferation while progesterone (P4) inhibits this response and causes differentiation of the cells. In this study, we identified the mechanism whereby E2 and P4 reciprocally regulate the expression of minichromosome maintenance (MCM)-2, a protein that is an essential component of the hexameric MCM-2 to 7 complex required for DNA synthesis initiation. We show in the uterine epithelium that Kruppel-like transcription (KLF) factors, KLF 4 and 15, are inversely expressed; most importantly, they bind to the Mcm2 promoter under the regulation of E2 and P4E2, respectively. After P4E2 exposure and in contrast to E2 treated mice, the Mcm2 promoter displays increased histone 3 (H3) methylation and the recruitment of histone deacetylase 1 and 3 with the concomitant deacetylation of H3. This increased methylation and decreased acetylation is associated with an inhibition of RNA polymerase II binding, indicating an inactive Mcm2 promoter following P4E2 treatment. Using transient transfection assays in the Ishikawa endometrial cell line, we demonstrate that Mcm2 promoter activity is hormonally stimulated by E2 and that KLF15 inhibits this E2 enhanced transcription. KLF15 expression also blocks Ishikawa cell proliferation through inhibition of MCM2 protein level. Importantly, in vivo expression of KLF15 in an estrogenized uterus mimics P4’s action by inhibiting E2-induced uterine epithelial MCM-2 expression and DNA synthesis. KLF15 is therefore a downstream physiological mediator of progesterone’s cell cycle inhibitory action in the uterine epithelium.
