雌激素受体ERα亚细胞定位及其与细胞生长的相关性

发布时间：2018-10-10 13:11

【摘要】： 雌激素受体(estrogen receptor,ER)是核受体超家族(nucleus receptor,NR)成员之一。作为一种激素受体,ER能够被其配体雌激素中的主要成分雌二醇(steroid hormone 17?-estradiol,E2 )激活。ER广泛地分布在雌性或雄性生殖系统、乳腺、中枢神经系统的部分区域里。同时,ER还参与细胞增殖、分化、凋亡等各种重要的生理调控过程。 ER可以分成ERα和ERβ两个亚型,它们都由4个不同的功能域组成,每个功能域都发挥不同的作用。这4个功能域分别是:转录激活区(A/B)、配体结合区(LBD)、铰链区(Hinge)和DNA结合区(DBD)。本文中,我们通过构建ERα的不同缺失突变体(ER△LBD、ER△DBD和ER△Hinge)来研究不同功能域在细胞增殖、亚细胞定位和E2刺激对ERα亚细胞定位的影响。结果表明,ERα呈核多浆少的分布、ER△LBD为核定位、ER△DBD为核多浆少分布、ER△Hinge主要分布在浆,核中有很少量。进一步分析表明,E2诱导的ERα入核是入核序列(NLS)依赖性。此外,我们还发现,ERα能够增强293Τ细胞增殖,且这种促增殖效应依赖于ERα在细胞核与胞浆的正常转运。视黄素X受体(retinoid X receptor, RXR)属于类固醇/甲状腺激素受体超家族成员,其配体视黄素(retinoids)是天然的或人工合成的维生素A衍生物。视黄素通过RXRs的介导在细胞生长、分化和凋亡过程中发挥重要的作用。RXRα能够与ERα结合形成异源二聚体,但RXRα在协助ERα转运过程中的作用未见报导。我们的研究表明,RXRα能够协助突变体ER△DBD和ER△Hinge出核,并且当E2处理细胞后,出核的ER△DBD又重新回到核中,而出核的ER△Hinge不受影响。结果提示,ERα不同功能域在与RXRα、E2作用时发挥不同的功能。总之,通过研究,我们确定了ERα不同功能域在其亚细胞定位、促细胞增殖中的作用,并且发现RXRα能够协助ER△DBD和ER△Hinge出核。这为我们进一步研究ERα和E2的作用机理以及更有效地防治乳腺癌提供了一些研究思路。
[Abstract]:Estrogen receptor (estrogen receptor,ER) is a member of nuclear receptor superfamily (nucleus receptor,NR). As a hormone receptor, ER can be activated by estradiol estradiolone E2, the main component of estrogen. ER is widely distributed in female or male reproductive system, mammary gland, and parts of central nervous system. At the same time, ER also participates in various important physiological regulation processes such as cell proliferation, differentiation and apoptosis. ER can be divided into two subtypes, ER 伪 and ER 尾, which are composed of four different functional domains, each of which plays a different role. The four functional domains are: transcriptional activation region (A- / B), ligand binding region (LBD), hinge region (Hinge) and DNA binding region (DBD). In this paper, we constructed different deletion mutants of ER 伪 (ER LBD,ER DBD and ER Hinge) to study the effects of different functional domains on the subcellular localization of ER 伪 in cell proliferation, subcellular localization and E2 stimulation. The results showed that the distribution of ER 伪 was less, that of ER LBD was nuclear localization, that of ER DBD was less than that of nucleus, and that of ER Hinge was mainly distributed in plasma, and there was a small amount of ER Hinge in nucleus. Further analysis showed that E2 induced ER 伪 nucleation was (NLS) dependent. In addition, we also found that ER 伪 can enhance the proliferation of 293T cells, and this proliferative effect depends on the normal transport of ER 伪 in nucleus and cytoplasm. Retinoid X receptor (retinoid X receptor, RXR) is a member of steroid / thyroid hormone receptor superfamily, and its ligand retinoid (retinoids) is a natural or synthetic vitamin A derivative. Retinin plays an important role in cell growth, differentiation and apoptosis through RXRs. RXR 伪 can bind with ER 伪 to form heterodimer, but the role of RXR 伪 in assisting ER 伪 transport has not been reported. Our results show that RXR 伪 can assist the nucleation of ER DBD and ER Hinge, and when E2 is treated, the ER DBD of the nucleation returns to the nucleus, but the ER Hinge of the nucleus is not affected. The results suggest that different functional domains of ER 伪 play different roles in the interaction with RXR 伪 and E2. In conclusion, we confirmed the role of different functional domains of ER 伪 in its subcellular localization and proliferation, and found that RXR 伪 can assist ER DBD and ER Hinge to produce nuclei. This provides us with some ideas for further study on the mechanism of ER 伪 and E2 and for more effective prevention and treatment of breast cancer.
【学位授予单位】：厦门大学
【学位级别】：硕士
【学位授予年份】：2006
【分类号】：R341

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