Global uterine Genomics in vivo:: Microarray evaluation of the estrogen receptor α-growth factor cross-talk mechanism
Global uterine Genomics in vivo:: Microarray evaluation of the estrogen receptor α-growth factor cross-talk mechanism
复制标题
DOI：
10.1210/me.2004-0142
复制
发表时间：
2005-03-01
影响因子：
--
通讯作者：
Korach, KS
中科院分区：
文献类型：
--
作者：
Hewitt, SC;Collins, J;Korach, KS
生长因子受体和雌激素受体(ER)之间的串扰被认为是雌激素靶组织中的一种信号机制，ERα是生长因子受体激活信号的直接靶点，导致雌激素靶基因和雌激素样生物反应对生长因子的调节。我们评估了小鼠子宫对表皮生长因子或IGF-I的整体基因组变化是否与雌二醇(E2)的变化相似，反映了串扰机制。野生型(WT)对生长因子和E2的重叠反应在野生型(WT)中预期，而在缺乏ERpha(ERpha基因敲除)的小鼠中预期不会有反应。令人惊讶的是，尽管WT中的大多数E2反应也发生在生长因子处理之后，但一些基因只被E2诱导。其次，虽然E2没有引起αER基因敲除中的基因变化，但生长因子的反应与WT的几乎没有区别。一些基因对IGF-I或表皮生长因子的反应差异表明了选择性调节机制，如磷脂酰肌醇3-激酶或MAPK依赖的反应。考虑到生物生长反应依赖于ERpha，这里观察到的对生长因子的强大的ERpha非依赖的基因组反应是令人惊讶的。我们提出了两种机制来替代子宫基因调控的串扰机制。首先，雌二醇会增加子宫生长因子，从而激活下游的信号级联，从而导致基因调控。其次，生长因子和雌激素调节相似的基因。我们的结果表明，子宫中的雌激素反应包括E2特异性的ERα介导的反应，以及生长因子和ER启动的活动的汇聚引起的反应。
Cross-talk between growth factor receptors and the estrogen receptor ( ER) has been proposed as a signaling mechanism in estrogen target tissues, with ERalpha as a direct target of growth factor receptor-activated signals, leading to regulation of estrogen target genes and estrogen-like biological responses to growth factors. We evaluated whether global genomic changes in the mouse uterus in response to epidermal growth factor or IGF-I mimic those of estradiol (E2), reflecting the cross-talk mechanism. Overlapping responses to growth factors and E2 were expected in the wild type (WT) whereas no response was expected in mice lacking ERalpha (ERalpha knockout). Surprisingly, although most of the E2 response in the WT also occurred after growth factor treatment, some genes were induced only by E2. Second, although E2 did not induce gene changes in the alphaER knockout, the growth factor response was almost indistinguishable from that of the WT. Differences in response of some genes to IGF-I or epidermal growth factor indicated selective regulation mechanisms, such as phosphatidylinositol 3-kinase or MAPK-dependent responses. The robust ERalpha-independent genomic response to growth factor observed here is surprising considering that the biological growth response is ERalpha dependent. We propose two mechanisms as alternatives to the cross-talk mechanism for uterine gene regulation. First, E2 increases uterine growth factors, which activate downstream signaling cascades, resulting in gene regulation. Second, growth factors and estrogen regulate similar genes. Our results suggest that the estrogen response in the uterus involves E2-specific ERalpha-mediated responses as well as responses resulting from convergence of growth factor and ER-initiated activities.