Department of Immunology, Central Eastern Clinical School, Monash University, Victoria 3800, Australia.
Protein Cell. 2011 Apr;2(4):333-46. doi: 10.1007/s13238-011-1033-2. Epub 2011 May 15.
Estrogen is implicated as playing an important role in aging and tumorigenesis of estrogen responsive tissues; however the mechanisms underlying the mitogenic actions of estrogen are not fully understood. Here we report that estrogen deficiency in mice caused by targeted disruption of the aromatase gene results in a significant inhibition of telomerase maintenance of telomeres in mouse ovaries in a tissue-specific manner. The inhibition entails a significant shortening of telomeres and compromised proliferation in the follicular granulosa cell compartment of ovary. Gene expression analysis showed decreased levels of proto-oncogene c-Myc and the telomerase catalytic subunit, telomerase reverse transcriptase (TERT), in response to estrogen deficiency. Estrogen replacement therapy led to increases in TERT gene expression, telomerase activity, telomere length and ovarian tissue growth, thereby reinstating ovary development to normal in four weeks. Our data demonstrate for the first time that telomere maintenance is the primary mechanism mediating the mitogenic effect of estrogen on ovarian granulosa cell proliferation by upregulating the genes of c-Myc and TERT in vivo. Estrogen deficiency or over-activity may cause ovarian tissue aging or tumorigenesis, respectively, through estrogen regulation of telomere remodeling.
雌激素被认为在雌激素反应组织的衰老和肿瘤发生中发挥重要作用；然而，雌激素的有丝分裂作用的机制尚未完全阐明。在这里，我们报告说，通过靶向破坏芳香酶基因导致的小鼠雌激素缺乏会以组织特异性的方式显着抑制小鼠卵巢中端粒酶维持端粒。这种抑制需要端粒的显着缩短和卵巢滤泡颗粒细胞区室的增殖受损。基因表达分析显示，对雌激素缺乏的反应，原癌基因 c-Myc 和端粒酶催化亚基端粒酶逆转录酶（TERT）的水平降低。雌激素替代疗法导致 TERT 基因表达、端粒酶活性、端粒长度和卵巢组织生长增加，从而在四周内将卵巢发育恢复正常。我们的数据首次表明，端粒维持是雌激素对卵巢颗粒细胞增殖有丝分裂作用的主要机制，通过在体内上调 c-Myc 和 TERT 的基因。雌激素缺乏或过度活跃可能分别通过雌激素调节端粒重塑导致卵巢组织衰老或肿瘤发生。
