Non-Steroidal Subtype Selective Estrogens

Veeneman, G. H.

doi:10.2174/0929867053764662

Cited by 58 publications

(23 citation statements)

References 80 publications

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“…Additional compounds have been developed and characterized to obtain more favorable tissue and receptor subtype selective effects (reviewed in Refs. 109,299). The term SERM (selective estrogen receptor modulator) describes synthetic ER ligands that display tissue-selective pharmacology.…”

Section: B Diverse Structures Of Synthetic Dietary and Environmentmentioning

confidence: 99%

Estrogen Receptors: How Do They Signal and What Are Their Targets

Heldring¹,

Pike²,

Andersson³

et al. 2007

Physiological Reviews

1,560

1,299

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During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ERα and ERβ) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.

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Section: B Diverse Structures Of Synthetic Dietary and Environmentmentioning

confidence: 99%

Estrogen Receptors: How Do They Signal and What Are Their Targets

Heldring¹,

Pike²,

Andersson³

et al. 2007

Physiological Reviews

1,560

1,299

View full text Add to dashboard Cite

show abstract

“…Moreover, a number of ER modulators have been developed that selectively bind ERα or ERβ (Veeneman, 2005). Diarylpropionitrile (DPN) is a subtype selective agonist with a 70-fold greater RBA and 170-fold greater relative potency in transcription assays for ERβ than for ERα (Meyers et al, 2001;Sun et al, 2003).…”

Section: Expression and Function Of Estrogen Receptorsmentioning

confidence: 99%

Estrogen receptor beta in the brain: From form to function

Weiser

Foradori

Handa

2008

Brain Research Reviews

197

159

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Estrogens have numerous effects on the brain, both in adulthood and during development. These actions of estrogen are mediated by two distinct estrogen receptor (ER) systems, ER alpha (ERα) and ER beta (ERβ). In brain, ERα plays a critical role in regulating reproductive neuroendocrine function and behavior, however, a definitive role for ERβ in any neurobiological function has been slow in forthcoming. Clues to the function of ERβ in the central nervous system can be gleaned from the neuroanatomical distribution of ERβ and the phenotypes of neurons that express ERβ. ERβ immunoreactivity has been found in populations of GnRH, CRH, vasopressin, oxytocin and prolactin containing neurons in the hypothalamus. Utilizing subtype-selective estrogen receptor agonists can help determine the roles for ERβ in non-reproductive behaviors in rat models. ERβ selective agonists exert potent anxiolytic activity when animals were tested in a number of behavioral paradigms. Consistent with this, ERβ selective agonists also inhibited the ACTH and corticosterone response to stress. In contrast, ERα selective agonists were found to be anxiogenic and correspondingly increased the hormonal stress response. Taken together, our studies implicate ERβ as an important modulator of some non-reproductive neurobiological systems. The molecular and neuroanatomical targets of estrogen that are mediated by ERβ remain to be determined.A number of splice variants of ERβ mRNA have been reported in brain tissue. Imaging of eGFP labeled chimeric receptor proteins transfected into cell lines show that ERβ splice variation can alter trafficking patterns and function. The originally described ERβ (herein termed ER-β1) is characterized by possessing a high affinity for estradiol. Similar to ERα, it is localized in the nucleus and is trafficked to nuclear sites termed "hyperspeckles" following ligand binding. In contrast, ER-β2 contains an 18 amino acid insert within the ligand binding domain and as a result can be best described as a low affinity form of ERβ. A delta3 (δ3) variant of ERβ has a deletion of the 3rd exon (coding for the second half of the DNA binding domain) and as a result does not bind an estrogen response element in DNA. δ3 variants are trafficked to a unique low abundance and larger nuclear site following ligand binding. A delta4 (δ4) variant lacks exon 4 and as a result is localized to the cytoplasm. The amount of individual splice variant mRNAs varies depending upon brain region. Examination of neuropeptide promoter regulation by ERβ splice variants demonstrate that ERβ functions as a constitutively active transcription factor. Moreover, it appears that splice variation of ERβ alters its ability to regulate transcription in a promoter-dependent and ligand-dependent fashion.

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“…It is therefore not surprising that most compounds tested so far bind to ERa and ERb with similar affinities or have similar potencies in activation of estrogen response element (ERE)-mediated reporter gene expression [22]. However, some ERa-or ERb-selective ligands have been identified [23].…”

Section: Estrogen Receptorsmentioning

confidence: 99%

A structural view of nuclear hormone receptor: endocrine disruptor interactions

Maire

Bourguet

Balaguer

2010

Cell. Mol. Life Sci.

114

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Endocrine-disrupting chemicals (EDCs) represent a broad class of exogenous substances that cause adverse effects in the endocrine system by interfering with hormone biosynthesis, metabolism, or action. The molecular mechanisms of EDCs involve different pathways including interactions with nuclear hormone receptors (NHRs) which are primary targets of a large variety of environmental contaminants. Here, based on the crystal structures currently available in the Protein Data Bank, we review recent studies showing the many ways in which EDCs interact with NHRs and impact their signaling pathways. Like the estrogenic chemical diethylstilbestrol, some EDCs mimic the natural hormones through conserved protein-ligand contacts, while others, such as organotins, employ radically different binding mechanisms. Such structure-based knowledge, in addition to providing a better understanding of EDC activities, can be used to predict the endocrine-disrupting potential of environmental pollutants and may have applications in drug discovery.

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Non-Steroidal Subtype Selective Estrogens

Cited by 58 publications

References 80 publications

Estrogen Receptors: How Do They Signal and What Are Their Targets

Estrogen Receptors: How Do They Signal and What Are Their Targets

Estrogen receptor beta in the brain: From form to function

A structural view of nuclear hormone receptor: endocrine disruptor interactions

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