17Beta-Estradiol Signaling and Regulation of Proliferation and Apoptosis of Rat Sertoli Cells1

Abstract

The aim of the present study was to investigate the intracellular signaling events downstream of the classical estrogen receptors (ESRs) and G protein-coupled estrogen receptor 1 (GPER) involved in regulation of proliferation and apoptosis of rat Sertoli cells, in which we have previously described ESR1, ESR2, and GPER. ESRs play a role in Sertoli cell proliferation, and GPER, but not ESRs, plays a role modulating gene expression involved with apoptosis. The present study shows that 17beta-estradiol (E2) and the GPER-selective agonist G-1 rapidly activate phosphatidylinositol 3-kinase (PIK3)/serine threonine protein kinase (AKT) and cyclic AMP response element-binding (CREB) phosphorylation. E2 and the ESR1-selective agonist 4,4',4″-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) increase the expression of cyclin D1 (CCND1), whereas the ESR2-selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) and G-1 do not change the expression of this protein, suggesting that ESR1 is the upstream receptor regulating Sertoli cell proliferation. E2- or PPT-ESR1, through activation of epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase 3/1 (MAPK3/1) and PIK3 pathways, induces upregulation of CCND1. KG-501, the compound that disrupts the phospho-CREB/CREB binding protein (CBP) complex, does not change E2- or PPT-ESR1-mediated CCND1 expression, suggesting that phospho-CREB/cyclic AMP response element/CBP is not involved in the expression of this protein. E2- or G-1-GPER, through activation of EGFR/MAPK3/1 and PIK3 pathways, may be involved in the upregulation of antiapoptotic proteins BCL2 and BCL2L2. E2- or G-1-GPER/EGFR/MAPK3/1/phospho-CREB decreases BAX expression. Taken together, these results show a differential effect of E2-GPER on the CREB-mediated transcription of proapoptotic and antiapoptotic genes of the same BCL2 gene family. ESR1 and GPER can mediate the rapid E2 actions in the Sertoli cells, which in turn can modulate nuclear transcriptional events important for Sertoli cell function and maintenance of normal testis development and homeostasis. Our findings are important to clarify the role of estrogen in a critical period of testicular development, and to direct further studies, which may contribute to better understanding of the causes of male infertility.

Effects of Elevated β-Estradiol Levels on the Functional Morphology of the Testis - New Insights

“…The function of estradiol varies depending on the cells in which it is being produced. In testicular cells, estradiol is known to regulate numerous aspects of spermatogenesis, including proliferation, differentiation, survival and apoptosis of germ cells1617181920. Estradiol is involved in the modulation of cell communication via the tight junctions of Sertoli cells and in the regulation of Leydig cell function2122232425.…”

Expression of Genomic Functional Estrogen Receptor 1 in Mouse Sertoli Cells

“…[22][23][24][25] A rapid estrogen-signaling cascade mediated by nonclassical membrane-associated ESRs in rat Sertoli cells has been recently characterized. 31,34,35 However, these studies do not differentiate whether the estrogen action is mediated by ERS1 or ESR2. Although our study focuses on the genomic action of ESR1 in mouse Sertoli cells, we do not exclude that a nonclassical membrane-associated ESR1 transduces rapid estrogen signals in mouse Sertoli cells.…”

“…2 This notion is concurred by a recent study in mice that estrogen-dependent ESR1 action is required for germ cell survival and most likely involves the support of Sertoli cell functions. 31 Sertoli cells are the somatic epithelial cells that line the seminiferous tubules of the testes in continuous contact with spermatogenic cells. It is known that these cells play critical roles in nursing and support of spermatogenic cell differentiation and maturation in response to a variety of hormone actions.…”

Interactions between oestrogen and 1α,25(OH)2-vitamin D3 signalling and their roles in spermatogenesis and spermatozoa functions

“…Oestrogens’ effects seem to depend on the cellular environment and estradiol concentration, as we have seen in cultures of adult rat seminiferous tubules, estradiol at 10 -9 M expresses a different regulation of cyclins A1 and B1 [82]. In cultured immature rat Sertoli cells, 17β-estradiol induces the translocation of oestrogen receptors ESR1 and ESR2 to the cell membrane, as well as MAPK3/1 phosphorylation and their proliferation [83] whereas the binding of estradiol to GPER mediates MAPK3/1 activation through G protein beta gamma subunits that promote SRC-mediated metalloprotease dependent release of EGFR ligands which regulate gene expression involved in apoptosis [19, 84]. The anti-apoptotic effect of 17β-estradiol in immature Sertoli cells was confirmed by Simoes et al [85].…”