Avenir Team Genetic and Physiology of the Onset of Puberty, Institut National de la Santé et de laRecherche Médicale Unité 676, Hopital Robert Debré, and Université Paris Diderot, 75019 Paris, France.
Endocrinology. 2010 Aug;151(8):3764-72. doi: 10.1210/en.2010-0260. Epub 2010 Jun 9.
Kisspeptins are hypothalamic neuropeptides encoded by KISS1 and recently described as major regulators of GnRH release from hypothalamic neurons. Although 17beta-estradiol (E2)-induced up-regulation of KISS1 expression has been documented in anteroventral periventricular nucleus neurons, E2 down-regulates KISS1 expression in arcuate nucleus neurons via the estrogen receptor alpha by unknown molecular mechanisms. Because KISS1 was initially described as a metastasis inhibitor, notably in breast tumors, we used the MDA-MB-231 breast cancer cell line, which expresses high levels of KISS1, to characterize the molecular mechanism underlying KISS1 regulation by E2. E2 rapidly down-regulated endogenous KISS1 in a stable ERalpha-expressing MDA-MB-231 cell line. Promoter analysis revealed that E2 down-regulation was determined by a short 93-bp sequence devoid of estrogen response element and Sp1 sites. E2 down-regulation persisted with an ERalpha that was unable to bind DNA and in the presence of histone deacetylase inhibitor. In the absence of E2, unliganded ERalpha and RNA polymerase II (RNAPII) were present on the proximal promoter. E2 stimulation induced recruitment of ERalpha and loss of RNAPII at the proximal promoter. Along the gene body, total RNAPII amounts were similar in E2-treated and untreated cells, whereas the active form was significantly less abundant in E2-treated cells. Thus, E2-induced down-regulation of KISS1 is mediated by a pathway combining RNAPII loss at the proximal promoter and modulation of active RNAPII along the gene body, which is a novel mechanism in the complex process of E2-induced repression of gene expression.
kisspeptins 是由 kiss1 编码的下丘脑神经肽，最近被描述为下丘脑神经元 gnrh 释放的主要调节剂。虽然已经证明 17β-雌二醇 (e2) 诱导前脑室旁核神经元 kiss1 表达上调，但 e2 通过未知的分子机制通过雌激素受体 α下调弓状核神经元中的 kiss1 表达。因为 kiss1 最初被描述为一种转移抑制剂，特别是在乳腺癌肿瘤中，我们使用了表达高水平 kiss1 的 mda-mb-231 乳腺癌细胞系，来表征 e2 调节 kiss1 的分子机制。e2 迅速下调稳定表达 eralpha 的 mda-mb-231 细胞系中的内源性 kiss1。启动子分析表明，e2 的下调是由一个缺乏雌激素反应元件和 sp1 位点的 93bp 短序列决定的。在不能结合 dna 的 eralpha 和组蛋白去乙酰化酶抑制剂存在的情况下，e2 的下调仍然持续。在没有 e2 的情况下，未配体结合的 eralpha 和 rnapii 存在于近端启动子上。e2 刺激诱导 eralpha 的募集和近端启动子上 rnapii 的丢失。沿着基因体，e2 处理和未处理细胞中的总 rnapii 量相似，而活性形式在 e2 处理细胞中明显较少。因此，e2 诱导的 kiss1 下调是由近端启动子上 rnapii 丢失和基因体上活性 rnapii 调节相结合的途径介导的，这是 e2 诱导基因表达抑制的复杂过程中的一种新机制。
