Estrogen Signaling Multiple Pathways to Impact Gene Transcription

Abstract

Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17 -estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-B (NF-B) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge.

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

“…Estrogen-bound ER translocates to the nucleus and initiates gene transcription by binding to estrogen response element (ERE) in the promoter region of target genes. Alternatively, ER interacts with other transcription factors, indirectly modulating gene expression (Marino et al, 2006). In addition to the nuclear action of ER, plasma membrane and cytoplasmlocalized ER activate multiple signaling pathways and exert rapid effects upon estrogen stimulation (Kampa et al, 2008;Levin and Pietras, 2008).…”

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

“…In humans, MAPK signaling is essential for tilting the gene expression balance towards SOX9 expression; gain- of-function mutations of MAP3K1 lead to higher phosphorylation of downstream targets, causing decreased expression of SOX9 and increased expression of female-specific genes like β-catenin. 2,31,32 In mice, the Mapk pathway acts through direct upregulation of Sry; homozygous loss-of-function variants of Map3k4 are reflected in a male-to-female sex reversal phenotype. 3,33 Nuclear receptor family members, to which the ERs belong, are known to exert their functions through different action mechanisms.…”

The Steroid Hormone 20-Hydroxyecdysone Enhances Gene Transcription through the cAMP Response Element-binding Protein (CREB) Signaling Pathway

“…The steroid hormones may activate PKC and PKA pathways. For example, estrogen increases calcium and activates PI3K/AKT and PLC/PKC signaling (72). Diethylstilbestrol induces the expression and activation of melaninrelated enzymes by activating cAMP/PKA signaling (73).…”