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 ERalpha is required for uterine responses to IGF-1 in vivo, both wild-type (WT) and ERalpha knockout (alphaERKO) mice were administered IGF-1, and various uterine responses to IGF-1 were compared. In both WT and alphaERKO 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 alphaERKO mice. However, IGF-1 treatment stimulated BrdUrd incorporation and proliferating cell nuclear antigen expression in WT uteri only. To determine whether ERalpha 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 alphaERKO mouse uterus, 2) ERalpha 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.
Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk / D. Klotz, S. Hewitt, P. Ciana, M. Raviscioni, J. Lindzey, J. Foley, A. Maggi, R. DiAugustine, K. Korach. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 277:10(2002), pp. 8531-8537.
|Titolo:||Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
Settore BIO/18 - Genetica
|Data di pubblicazione:||2002|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1074/jbc.M109592200|
|Appare nelle tipologie:||01 - Articolo su periodico|