Requirement of Estrogen Receptor-α in Insulin-like Growth Factor-1 (IGF-1)-induced Uterine Responses and in Vivo Evidence for IGF-1/Estrogen Receptor Cross-talk

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␣ is required for uterine responses to IGF-1 in vivo, both wild-type (WT) and ER␣ knockout (␣ERKO) mice were administered IGF-1, and various uterine responses to IGF-1 were compared. In both WT and ␣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 ␣ERKO mice. However, IGF-1 treatment stimulated BrdUrd incorporation and proliferating cell nuclear antigen expression in WT uteri only. To determine whether ER␣ 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 ␣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.Epithelial cells of the mammalian uterus undergo a wave of DNA synthesis followed by mitosis in response to 17␤-estradiol (E 2 ), 1 which regulates the transcription of numerous target genes by binding to and activating the nuclear estrogen receptor (ER). Among the genes identified as targets for regulation by the E 2 /ER complex in the uterus is that encoding insulinlike growth factor-1 (IGF-1). Studies have demonstrated that rodent uterine IGF-1 mRNA levels increase after exposure to E 2 (1, 2). Furthermore, presumably through increasing local production of IGF-1, E 2 has been shown to stimulate uterine IGF-1 receptor (IGF-1R) signaling as measured by tyrosine phosphorylation of IGF-1R and the formation of a signaling complex composed of IGF-1R, insulin receptor substrate-1 (IRS-1), and p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase) (3, 4). These studies suggested that IGF-1 signaling is involved in E 2 -induced uterine growth, and in support of this mechanism, other studies have shown that, like E 2 , IGF-1 can induce DNA synthesis in cells of the rodent uterus (5). A more recent study further demonstrated a role for IGF-1 in E 2 -induced uterine proliferation by demonstrating that IGF-1 is required for E 2 -induced uterine epithelial cell mitosis (6). In that study, DNA synthesis occurred in IGF-1 knockout (IGF-1KO) m...

Evolution of adrenal and sex steroid action in vertebrates: a ligand‐based mechanism for complexity

“…Examples are insulin-like growth factor, epidermal growth factor, and transforming growth factor-beta, which act by binding to receptors on the cell membrane, and c-Fos and c-Jun, transcription factors that bind to AP-1 sites [9][10][11]25]. Cross-talk between these proteins and the five steroid receptors increases the combinatorial complexity for regulation of development in vertebrates.…”

“…1) [5][6][7][8], which is a ligand-based based mechanism for regulating the interactions between networks of transcription factors [9][10][11], as well as directly regulating the transcription of specific genes. Receptors for these steroids have not been found in invertebrates.…”

Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation

“…IGF-1 stimulates mitogenesis of the normal epithelium and proliferation of both endometrial cancers and leiomyoma cells (Strawn et al, 1995;Klotz et al, 2000). In the mouse uterine model, the in vivo proliferative response of IGF-1 requires ERa, even in the presence of a functional IGF-1 signaling response, as IGF-1 signaling to MAPK or Akt is unaffected by the loss of ER (Klotz et al, 2002). In the uterus, E2 increases the levels of IGF-1 mRNA, and stimulates tyrosine phosphorylation of the IGF-1 receptor and insulin receptor substrate-1, and the formation of IGF-1R signaling complexes (Richards et al, 1996;Klotz et al, 2000).…”

Molecular Mechanisms of Bladder Outlet Obstruction in Transgenic Male Mice Overexpressing Aromatase (Cyp19a1)

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