Estrogen-receptors activation mechanisms

Kiss Z (1994) Tamoxifen stimulates phospholipase D activity by an estrogen receptor-independent mechanism. FEBS Lett 355 173-177... 

The mechanisms of corticosteroid receptor regulation of transcription have been elucidated. Both type I and type II corticosteroid receptors are members of a superfamily of ligand-activated transcription factors defined by protein sequence similarity. Included in this superfamily are various other steroid receptors, such as the estrogen receptor, as well as members of the retinoic acid receptor... 

Simoncini T, Genazzani AR, Liao JK (2002a) Nongenomic mechanisms of endothelial nitric oxide synthetase activation by the selective estrogen receptor modulator raloxifene. Circulation 105 1368-1373... 

Fig. 6.2. Proposed mechanisms of action of pure antiestrogens (fulvestrant). 1 Fulvestrant (ICI) binds to estrogen receptor (ER). 2 Fulvestrant binding to ER accelerates receptor degradation ( ER down-regulator ). 3 Rate of dimerization and nuclear localization of fulvestrant-ER complex is reduced. 4 Reduced binding of fulvestrant-ER to ERE. 5 No transcription of estrogen-responsive genes since AF-1 and AF-2 are inactive, no coactivators are recruited and the activity of RNA polymerase II is not activated (or inhibited) (Wakeling 2000)...

Figure 25.3 Presentation of estradiol to A. endothelial cells affects signaling. (A) Physiological levels of estradiol (E2) complexed with albumin do not elicit the production of nitric oxide when presented to cultured endothelial cells although E2-albumin binds to caveolar SR-B1. (B) Physiological levels of estradiol complexed with HDL elicit the production of nitric oxide by activating AMPK and then eNOS. Although it is depicted in this figure that AMPK is activated by binding of estradiol to the estrogen receptor, B. this mechanism has not been experimentally demonstrated. Other mechanisms of E2-HDL activation of AMPK and eNOS are thus possible (See also color insert).

The mechanisms by which thyroid hormones enhance antidepressant activity are still unknown. It is of interest that thyroid hormone increases net activity of several neurotransmitters that are putatively involved in the pathophysiology of depression in a way that is descriptively similar to that of estrogens. Receptors for the two hormones belong to the same superfamily. As was previously mentioned [Pfaff 1996], these issues are currently being explored, and clarifications are expected shortly. 

Due to the complex structure of the initiation complex it remains imclear which interactions are responsible for the first mechanism. The coupling between the transactivat-ing domain and the initiation complex can be direct or indirect. There is evidence which indicates that proteins with co-activator function mediate the interaction between HRE-bound receptors and the transcription initiation apparatus. One such protein is RIP-140, which mediates the transcription activation of the estrogen receptor. The AF2 domain can also directly contact the transcriptional apparatus. One component of the RNA polymerase II holoenzyme, the SUGl protein, has been identified as a binding partner for the AF2 domain. The SUGl protein has the function of a co-acti-vator in transcription initiation and is considered a mediator (see 1.4.3.2). 

There has also been a report of activation of the estrogen receptor mediated by the neurotransmitter dopamine (Power et al., 1991). This mechanism of activation is independent of that by the hormone. 

III. The Estrogen Receptors and Their Multiple Gene Activation Mechanisms. . 303... 

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