Rajkumar K, Dheen T, Krsek M, Murphy L J
Department of Internal Medicine, University of Manitoba, Winnipeg R3E 0W3 Canada.
Endocrinology. 1996 Apr;137(4):1258-64. doi: 10.1210/endo.137.4.8625897.
Insulin-like growth factor-I (IGF-I) has been implicated as autocrine/paracrine mediator of estrogen action in the rodent uterus. Here, we examined the effects of 17-beta estradiol (E2), epidermal growth factor (EGF), and IGF-I on DNA synthesis in the uterus of ovariectomized (ovex) transgenic mice (Tg), which overexpress rat insulin-like growth factor binding protein-1 (IGFBP-1). Litter size was significantly reduced in Tg mice compared with wild-type mice. Immunohistochemical studies localized the expression of the transgene to the luminal and glandular epithelium. In addition, rat IGFBP-1 immunoreactivity was present in luminal secretions. E2-induced uterine DNA synthesis as measured by methyl-3H thymidine incorporation, was significantly reduced in ovex Tg mice; 4.77 +/- 0.59 and 4.97 +/- 0.53 for Tg strains 57C and 277A, respectively, compared with 8.65 +/- 0.73 fmol/microgram of DNA for Wt mice. Similarly, uterine weight after three daily injections of E2 was reduced in Tg mice compared with Wt mice; 2.85 +/- 0.39 vs. 4.23 +/- 0.26 mg/g BW, P < 0.01. Semiquantitative RT-PCR assays were used to demonstrate changes in uterine IGF-I messenger RNA (mRNA) and EGF mRNA abundance after administration of E2. An approximately 3-fold increase in IGF-I mRNA abundance was seen 6 h after E2 in both Tg and Wt mice. Over the same time course, little change was seen in EGF mRNA levels, which were similar in Tg and Wt mice. After 3 days of E2 treatment, an increase in EGF mRNA was apparent in Wt mice but not in Tg mice. The uterine DNA response to both IGF-I and EGF was significantly attenuated in Tg mice compared with Wt mice. The data reported here together with previous reports of E2 regulation of IGF-I and IGFBP-1 expression in uterus support the hypothesis that the IGF-I is a mediator of estrogen action in the uterus. In addition attenuation of the EGF response in the uterine tissue of Tg mice suggests that this response is also mediated, in part, by IGF-I.
胰岛素样生长因子-I（IGF-I）被认为是啮齿动物子宫中雌激素作用的自分泌/旁分泌介质。在此，我们研究了17-β雌二醇（E2）、表皮生长因子（EGF）和IGF-I对去卵巢（ovex）的过表达大鼠胰岛素样生长因子结合蛋白-1（IGFBP-1）的转基因小鼠（Tg）子宫中DNA合成的影响。与野生型小鼠相比，Tg小鼠的窝仔数显著减少。免疫组织化学研究将转基因的表达定位在腔上皮和腺上皮。此外，腔分泌物中存在大鼠IGFBP-1免疫反应性。通过甲基-3H胸苷掺入法测定，E2诱导的子宫DNA合成在去卵巢Tg小鼠中显著降低；Tg品系57C和277A分别为4.77±0.59和4.97±0.53，而野生型小鼠为8.65±0.73 fmol/μg DNA。同样，与野生型小鼠相比，Tg小鼠在每日注射E2三天后的子宫重量降低；分别为2.85±0.39和4.23±0.26 mg/g体重，P<0.01。使用半定量RT-PCR分析来证明给予E2后子宫IGF-I信使核糖核酸（mRNA）和EGF mRNA丰度的变化。在E2处理6小时后，Tg小鼠和野生型小鼠的IGF-I mRNA丰度均增加了约3倍。在相同的时间进程中，EGF mRNA水平几乎没有变化，Tg小鼠和野生型小鼠中的水平相似。在E2处理3天后，野生型小鼠中EGF mRNA明显增加，而Tg小鼠中则没有。与野生型小鼠相比，Tg小鼠子宫对IGF-I和EGF的DNA反应均显著减弱。此处报告的数据以及先前关于E2对子宫中IGF-I和IGFBP-1表达调节的报告支持了IGF-I是子宫中雌激素作用介质的假说。此外，Tg小鼠子宫组织中EGF反应的减弱表明该反应也部分由IGF-I介导。
