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Submitted on April 6, 2004
Accepted on October 26, 2004
-growth factor cross talk mechanism
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology; Microarray Group; National Institute of Environmental Health Sciences; Research Triangle Park, North Carolina
* To whom correspondence should be addressed. E-mail: curtiss{at}niehs.nih.gov.
Cross-talk between growth factor receptors and the estrogen receptor has been proposed as a signaling mechanism in estrogen target tissues, with ER
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 EGF 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) while no response was expected in mice lacking ER (ERKO). Surprisingly, although most of the E2 response in the WT also occurred after growth factor treatment, some genes were induced only by E2. Secondly, although E2 did not induce gene changes in the ERKO, the growth factor response was almost indistinguishable from that of the WT. Differences in response of some genes to IGF-I or EGF indicated selective regulation mechanisms, such as PI3 kinase or MAP kinase dependent responses. The robust ER independent genomic response to GF observed here is surprising considering that the biological growth response is ER 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. Secondly, growth factors and estrogen regulate similar genes. Our results suggest that the estrogen response in the uterus involves E2-specific ER mediated responses as well as responses resulting from convergence of growth factor and ER initiated activities.
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