Abstract
In the uterus insulin-like growth factor-1 (IGF-1) signaling can be initiated by estradiol acting through its nuclear receptor (estrogen receptor (ER)) to stimulate the local synthesis of IGF-1. Conversely, in vitro studies have demonstrated that estradiol-independent ER transcriptional activity can be induced by IGF-1 signaling, providing evidence for a cross-talk mechanism between IGF-1 and ER. To investigate whether ER alpha is required for uterine responses to IGF-1 in vivo, both wild-type (WT) and ER alpha knockout (alpha ERKO) mice were administered IGF-1, and various uterine responses to IGF-1 were compared. In both WT and alpha ERKO mice, IGF-1 treatment resulted in phosphorylation of uterine IGF-1 receptor (IGF-1R) and formation of an IGF-1R/insulin receptor substrate-1/ phosphatidylinositol 3-kinase signaling complex. In addition, IGF-1 stimulated phosphorylation of uterine Akt and MAPK in both WT and alpha ERKO mice. However, IGF-1 treatment stimulated BrdUrd incorporation and proliferating cell nuclear antigen expression in WT uteri only. To determine whether ER alpha can be activated in vivo by IGF-1 signaling, transgenic mice carrying a luciferase gene driven by two estrogen response elements (ERE-luciferase mice) were utilized. Treatment of ovariectomized ERE-luciferase mice with IGF-1 resulted in an increase in uterine luciferase activity that was attenuated in the presence of the ER antagonist ICI 182,780. Together these data demonstrate that 1) functional signaling proximal to IGF-1R is maintained in the alpha ERKO mouse uterus, 2) ER alpha is necessary for IGF-1 induction of uterine nuclear proliferative responses, and 3) cross-talk between IGF-1R and ER signaling pathways exists in vivo.
Highlights
In the uterus insulin-like growth factor-1 (IGF-1) signaling can be initiated by estradiol acting through its nuclear receptor (estrogen receptor (ER)) to stimulate the local synthesis of IGF-1
Analysis of Estrogen- and IGF-1-stimulated Uterine DNA Synthesis and PCNA Expression—One indication of estrogen activity is the wave of DNA synthesis and mitosis that occurs in the uterine epithelium following administration of hormone. [3H]thymidine incorporation has been shown to increase to a maximal level at ϳ16 h following E2 treatment of ovariectomized mice [12]
The response was decreased compared with that of the E2 treatment group (Fig. 1A). This confirms that IGF-1 signaling initiates an estrogen-like DNA synthesis response in the uterine epithelium and that the response to this particular method of long R3 IGF-1 treatment is less extensive than the response to E2
Summary
Vol 277, No 10, Issue of March 8, pp. 8531–8537, 2002 Printed in U.S.A. Requirement of Estrogen Receptor-␣ in Insulin-like Growth Factor-1 (IGF-1)-induced Uterine Responses and in Vivo Evidence for IGF-1/Estrogen Receptor Cross-talk*. Treatment of ovariectomized ERE-luciferase mice with IGF-1 resulted in an increase in uterine luciferase activity that was attenuated in the presence of the ER antagonist ICI 182,780 Together these data demonstrate that 1) functional signaling proximal to IGF-1R is maintained in the ␣ERKO mouse uterus, 2) ER␣ is necessary for IGF-1 induction of uterine nuclear proliferative responses, and 3) cross-talk between IGF-1R and ER signaling pathways exists in vivo. In an effort to further understand the cross-talk between the IGF-1/IGF-1R and E2/ ER␣ signaling pathways, the current study was designed to evaluate the in vivo role of ER␣ in IGF-1-mediated uterine responses By utilizing both the ER␣ knockout (␣ERKO) and ERE-luciferase mouse models, we establish the requirement for ER␣ in IGF-1-induced uterine nuclear responses and provide in vivo molecular evidence demonstrating the existence of cross-talk between the uterine IGF-1 and ER signaling pathways
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
