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Estrogen Signaling Pathway


Figure 1. Estrogen signaling pathway.

Estrogen overview

The estrogen signaling pathway refers to all proteins of estrogen function and related regulatory proteins. Estrogen is a substance that promotes the development of secondary sexual characteristics and sexual organ maturation in female animals. It is secreted by the ovary and placenta of female animals. The receptors for estrogen are distributed in the uterus, vagina, breast, pelvis, skin, bladder, urethra, bones, and brain. Therefore, estrogen has a wide and important physiological role, which can promote and maintain the second sexual characteristics of female reproductive organs. The physiological effects have obvious impacts on endocrine, cardiovascular, metabolic systems, bone growth and maturation, and skin. Natural estrogen is mainly estradiol, estrone, and estriol. Currently, estrogen drugs commonly used in clinical practice are artificially synthesized derivatives of estradiol, such as estradiol benzoate and estradiol pentoxide. The role of estrogen in the cardiovascular system is mainly to regulate vascular function, and participate in the inflammatory response, metabolism, survival of cardiomyocytes and stem cells. Estrogen works mainly by binding to estrogen receptor (ER). When estrogen binds to ER, it regulates gene transcription in the nucleus or activates kinases in the cytoplasm to play its role. Understanding the estrogen signaling pathway will provide a theoretical basis for the prevention, diagnosis, and treatment of breast cancer, ovarian cancer, and other diseases.

Estrogen family

Estrogen works by binding to the ER. ER includes two types: ERα and ERβ, and the two receptors are highly homologous. A study found that the DNA binding domain of ERα and ERβ has 97% homology, and the ligand binding domain also has 60% homology. However, ERα and ERβ have different N-terminal transcriptional control domains. ER in the nuclear nucleus directly binds to DNA or regulates gene expression by indirect binding of other transcription factors to DNA. ER on the plasma membrane activates the PI3K signaling pathway. Estrogen not only regulates gene transcription but also binds to the ER on the cell membrane to activate the PI3K signaling pathway. The 447-cysteine site of ERα is capable of palletization and this effect is related to caveolin. Estrogen also binds to the G-protein coupled receptor (GPR30) and activates the PI3K and MAPK signaling pathways. In 2009, Deschamps and other studies showed that activation of GPR30 can reduce cerebral ischemia-reperfusion injury; In 2010, Jessup et al found that activation of GPR30 can reduce cardiac remodeling in autoimmune mice; in 2010, estrogen was found to promote endothelial cell proliferation and metastasis through GPR30.

Estrogen signaling pathway

  1. Estrogen signal pathway cascade

    The transmission of the estrogen signaling pathway mainly includes activation of estrogen receptors and signal transduction. Activation of the receptor mainly includes classic ligand-dependent ER activation: in the absence of hormones, ER is present in the target cell as a polyprotein inhibitory complex. The binding of estrogen to the receptor BLD enables homodimerization of the receptor and binding of its DBD to the estrogen response element (EREs) on the target gene, thereby cis-activating the enhancer of the target gene regulatory region, and promoting transcription of target genes. ER transcriptional activity is mediated by two independent non-acidic activation domains: the constitutive activation domain AF-1 at the N-terminus and the hormone-dependent AF-2 at LBD. Their transcriptional activity depends on the recruitment of synergistic factors. AF-l and AF-2 generally function in a coordinated manner. There is also an AF-2 functional domain in Ep, but its transcriptional activation mechanism is still unclear. Human ERp lacks AF-1, while mouse ER p has AF-1, and is similar in sequence and function to AR-1 of ER. It has been found that ER has more than 30 synergistic activation factors, many of which are shared by nuclear receptors. Different combinations of synergistic activators determine the tissue specificity of ER for target gene activation. Conversely, ERE with different sequences can also regulate the recruitment of ER to synergistic activators, thus affecting the transcriptional activity of ER. The regulation of estrogen can be divided into the following two of nuclear initiation of estrogen signaling pathway, which includes: a. ER directly binds to DNA: ERα and ERβ are a class of ligand-gated receptors that regulate gene expression. Estrogen binds to the AF2 domain of ER and leads to ER dimerization and binding to ER response elements (ERE) on DNA to enhance or inhibit gene expression. Therefore, estrogen-ER response complexes may have different roles in cell. Co-activators bind to different nuclear receptors, and since different ligands have different conformations, co-regulatory factors act dependent on the ligand binding domain. For example, Tamoxifen is an agonist of ER in the endometrium (recruiting activating factor), but an antagonist of ER (recruitment inhibitor) in the mammary gland. b. ER is not directly bound to DNA: ER can Direct regulation of gene transcription. And activates the PI3K and MAPK signaling pathways.

  2. Regulation of the estrogen signaling pathway:

    Even in the same tissues, ERα and ERβ have different gene expression. For example, in vascular smooth muscle cells, ERβ promotes and ERα inhibits the expression of nitric oxide synthase (NOS). ER also regulates different gene transcription in the mouse aorta. After removing endogenous estrogen from ERα/ERβ-deficient mice, estrogen was injected into the mice, and it was found that ERα up-regulated gene expression, while ERβ down-regulated gene expression. However, after treatment with ERβ inhibitor for 2 h, it was found that ERβ up-regulated 122 genes in the mouse heart and only 23 genes were down-regulated. Many experiments have shown that estrogen regulates gene transcription in a time-dependent manner. Gene transcriptions that differ between ERα and ERβ regulation may be associated with coactivators and co-suppressors. Numerous studies have shown that ERβ regulates different gene expression in different tissues. Estrogen regulates the expression of various genes, such as peroxidase, cadherin, adenine nuclear transcription factor, heat shock protein, and phosphatase inhibitor. ERα and ERβ regulate different gene expression, and therefore, factors that regulate the expression or activation of ERα and ERβ have attracted much attention. It is well known that ERα up-regulates some gene expression, while ERβ down-regulates or does not affect the expression of this gene. Therefore, altering the expression of ERα or ERβ may affect the expression of other genes. GPR30 or other cell membrane receptors may also alter gene expression through their phosphorylation. Studies have shown that GPR30 activation promotes the expression of novel ERα. The expression of ERα and ERβ is different in different cells. In cardiomyocytes, there was no significant gender difference in the expression of ERβ, but there was a significant gender difference in the expression of ERα. Long-term treatment of vascular tissue with estrogen revealed an increase in the expression of ERα and a decrease in the expression of ERβ.

  3. Relationship with disease

    Breast cancer

    Breast cancer is an estrogen-dependent tumor. It is believed that estrogen plays an important role in the development of breast cancer, and estrogen must be mediated through the estrogen receptor (ER). ER includes estrogen receptor alpha (ERα) and estrogen receptor β (ERβ), a nuclear transcription factor encoded by its gene. ER-related genes include ERα gene and ERβ gene, and related studies show that ERα gene expression loss or mutation is associated with poor prognosis of breast cancer. However, the related studies on the relationship between ERβ gene expression and prognosis of breast cancer are not consistent, and gene polymorphism may affect the expression level or function of ER in different individuals, and thus affect the biological effects.

    Gastric cancer

    ER-α36 and ER-α66 mRNA were expressed in gastric cancer cell lines and human gastric cancer samples. The expression of ER-α36 in gastric cancer cell lines was higher than that of ER-α66. The expression of ER-α66 was the highest in normal tissues, and the expression of ER-α36 was the highest in cancer tissues, and correlated with the age, tumor size, and lymph node metastasis. Therefore, the role of ER-α36 in gastric cancer cells may be greater than that of ER-α66, and the high expression of ER-α36 mRNA is related to the biological behavior of gastric cancer.

    Atherosclerosis

    The use of estrogen to prevent and treat atherosclerosis (AS) has become a hot topic in recent years. Studies have shown that the mechanism of estrogen anti-AS is mostly related to the regulation of vascular endothelium, vascular smooth muscle, blood lipids and anticoagulation. The immuno-inflammation theory of AS provides new ideas for studying the mechanism of anti-AS.

References:

  1. Ticconi C, Pietropolli A, Piccione E. Estrogen replacement therapy and asthma. Pulmonary Pharmacology & Therapeutics. 2013, 26(6):617-623.
  2. Velarde M C. Pleiotropic actions of estrogen: a mitochondrial matter. Physiological Genomics. 2013, 45(3):106-109.
  3. Obiorah I, Sengupta S, Curpan R, et al. Defining the conformation of the estrogen receptor complex that controls estrogen-induced apoptosis in breast cancer. Molecular Pharmacology. 2015, 85(5):789-99.
  4. Li X, Gao Y, Guo L H, et al. Structure-dependent activities of hydroxylated polybrominated diphenyl ethers on human estrogen receptor. Toxicology. 2013, 309(2):15-22.
  5. Singh R, Pallagatti S, Sheikh S, et al. Correlation of serum oestrogen with salivary calcium in post-menopausal women with and without oral dryness feeling. Gerodontology. 2012, 29(2):125-129.

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