5月9日，Yeshiva大學(xué)愛因斯坦醫(yī)學(xué)院的研究人員已經(jīng)發(fā)現(xiàn)一種能抑制雌激素作用的分子,。雌性激素的增長,，對生長、生殖組織的修復(fù)和子宮內(nèi)膜癌和乳腺癌的發(fā)展起著關(guān)鍵作用。動物實驗中發(fā)現(xiàn),，這一分子研究發(fā)現(xiàn)可能會帶來用于預(yù)防和治療人類的雌激素有關(guān)的疾病的新療法。研究結(jié)果發(fā)表在PNAS雜志上,。
激素雌二醇（雌激素的最重要的形式）和孕激素是為懷孕子宮服務(wù)的,。他們引發(fā)了一系列的細胞增殖和細胞分化事件，為受精卵植入子宮內(nèi)膜（子宮內(nèi)膜）提供良好環(huán)境,。雖然這個過程中受到嚴格控制,，但有時子宮細胞會異常增生，導(dǎo)致月經(jīng)紊亂,、子宮內(nèi)膜息肉,、子宮內(nèi)膜異位癥或子宮內(nèi)膜癌等，子宮內(nèi)膜癌是最常見的女性生殖道惡性腫瘤,。
Jeffrey Pollard,博士說：這些疾病背后的分子機制仍是個謎,，同時激素調(diào)節(jié)的子宮內(nèi)膜正常細胞的增殖的機制也不明確。
嚙齒動物研究中,， Pollard博士發(fā)現(xiàn),， KLF15（Kruppel樣轉(zhuǎn)錄因子-15）控制雌二醇和孕激素在子宮內(nèi)膜抑制MCM2的生成，MCM2參與DNA的合成過程,。
Pollard博士說：我們的研究結(jié)果可能為預(yù)防或治療子宮內(nèi)膜癌和乳腺癌提供可能性,，通過促進KLF15能治療雌激素有關(guān)的癌癥和其他疾病。（生物谷：Bioon.com）
doi:10.1073/pnas.1118515109
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PMID:
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.
