Differences in the binding mechanism of RU486 and progesterone to the progesterone receptor

Skafar, Debra F.

doi:10.1021/bi00109a003

Cited by 31 publications

(11 citation statements)

References 24 publications

(37 reference statements)

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“…In contrast, this study provides strong evidence that P acts through its own nuclear receptor to inhibit GnRH secretion: RU486 completely blocks the inhibitory effect of P on LH secretion. Although RU486 may exhibit mixed antagonist͞ agonist properties in other species (47,48), our study shows that it is purely antagonistic of P actions in the ovine neuroendocrine axis and has no effect on its own.…”

Section: Discussionmentioning

confidence: 58%

The negative feedback actions of progesterone on gonadotropinreleasing hormone secretion are transduced by the classical progesterone receptor

Skinner

Evans

Delaleu

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

142

122

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Progesterone (P) powerfully inhibits gonadotropin-releasing hormone (GnRH) secretion in ewes, as in other species, but the neural mechanisms underlying this effect remain poorly understood. Using an estrogen (E)-free ovine model, we investigated the immediate GnRH and luteinizing hormone (LH) response to acute manipulations of circulating P concentrations and whether this response was mediated by the nuclear P receptor. Simultaneous hypophyseal portal and jugular blood samples were collected over 36 hr: 0-12 hr, in the presence of exogenous P (P treatment begun 8 days earlier); 12-24 hr, P implant removed; 24-36 hr, P implant reinserted. P removal caused a significant rapid increase in the GnRH pulse frequency, which was detectable within two pulses (175 min). P insertion suppressed the GnRH pulse frequency even faster: the effect detectable within one pulse (49 min). LH pulsatility was modulated identically. The next two experiments demonstrated that these effects of P are mediated by the nuclear P receptor since intracerebroventricularly infused P suppressed LH release but 3␣-hydroxy-5␣-pregnan-20-one, which operates through the type A ␥-aminobutyric acid receptor, was without effect and pretreatment with the P-receptor antagonist RU486 blocked the ability of P to inhibit LH. Our final study showed that P exerts its acute suppression of GnRH through an E-dependent system because the effects of P on LH secretion, lost after long-term E deprivation, are restored after 2 weeks of E treatment. Thus we demonstrate that P acutely inhibits GnRH through an E-dependent nuclear P-receptor system. Progesterone (P) is the dominant ovarian steroid present in the peripheral circulation during the mammalian reproductive cycle and serves a number of important regulatory roles. The luteal phase elevation in P inhibits pulsatile gonadotropinreleasing hormone (GnRH) and luteinizing hormone (LH) secretion (1-4) and prevents the occurrence of GnRH (5) and LH (6, 7) surges in response to fluctuations in peripheral estrogen (E) levels that accompany the waves of follicular growth occurring in the ovary (8). We have also recently demonstrated that the luteal phase elevation of P affects both the timing of the LH surge relative to E stimulation and the magnitude of the coincident GnRH surge (D.C.S., N.P.E., and A.C., unpublished results). Despite its obvious importance in regulating reproduction, little is known about how and where P acts to powerfully inhibit the neuroendocrine reproductive axis.Our first study, using the hypophyseal portal cannulation approach, assessed directly the timing of the changes in GnRH secretion that follow both an abrupt decrease and an increase in circulating P concentrations. To avoid potential P-E interactions, short-term ovariectomized (OVX) ewes were used.Since P modulates tonic LH secretion by affecting GnRH pulse frequency (1-4), it is held that P acts through neural targets and putative candidates include the opioidergic, noradrenergic, and ␥-aminobutyric acid (GABA) systems (9, 10). The p...

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Section: Discussionmentioning

confidence: 58%

The negative feedback actions of progesterone on gonadotropinreleasing hormone secretion are transduced by the classical progesterone receptor

Skinner

Evans

Delaleu

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

142

122

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“…[11][12][13] Cooperativity is a universally important phenomenon in biological systems. 36) Other nuclear receptors, such as progesterone receptor 37) and vitamin D receptor, 38) show a similar transcriptional mechanism with positive cooperative binding with each ligand, dimerization and interaction with coactivators. In particular, a competitive binding assay using [ 3 H]-progesterone showed a steeper competition curve for RU486, the antagonist, than for progesterone.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Coactivator Recruitment by Cooperative Ligand Binding to Human Estrogen Receptor .ALPHA. and .BETA.

Suzuki

Nishida

Ohno

et al. 2007

Biological & Pharmaceutical Bulletin

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Estrogen receptor (ER) is a member of the nuclear receptor superfamily, and functions as a ligand-dependent transcription factor with roles in cell growth and differentiation. In addition to endogenous estrogen, 17b bestradiol (E 2 ) and artificial antagonists, many suspected environmental estrogenic chemicals are reported to bind to ER, with various affinities and transcriptional responses. ER is also an allosteric protein and shows a positive cooperative interaction with E 2 . Cooperativity affects inter-subunit interaction, and while ligand-bound ER interacts with coactivators, antagonist-bound ER does not. We therefore hypothesized that ligand-binding characteristics influence coactivator recruitment to the ER dimer, and thereby affect transcriptional activity. We investigated the interaction between ER and human Steroid Receptor Coactivator-1 (SRC-1), in the presence of compounds exhibiting various Hill coefficients. In the case of both ER subtypes (ERa a and ERb b), the Hill coefficients of the compounds tested correlated with the affinity of the ER-ligand complex to SRC-1, with the exception of ERb b-4-n-nonylphenol and ER-antagonist complexes. This is the first report to investigate the relationship between Hill coefficients of ligand binding and coactivator interaction with the ER-ligand complex. We also examined the proteolytic digestion of ER using trypsin, in the presence and absence of compounds with various Hill coefficients, to investigate ligand-dependent conformational changes in ER. We used not only agonists and antagonists but also compounds of weak biological activity (partial agonists). Our results shed light on the subtle modulation of transcriptional activation by chemical agents.

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“…A similar agonist effect is observed when PR-B is activated by PKA (Beck et al 1993), but this does not occur when it binds to PR-A (Meyer et al 1990). MFP induces PR dimerization and DNA binding with an affinity higher than that of progesterone, the natural ligand (DeMarzo et al 1991, Skafar 1991. The inhibitory effect of MFP is related to its ability to recruit corepressors (Jackson et al 1997).…”

Section: Progesterone Receptorsmentioning

confidence: 88%

Antiprogestins in breast cancer treatment: are we ready?

Lanari

Wargon²,

Rojas³

et al. 2012

Endocrine-Related Cancer

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Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. It is accepted that breast cancer is not a single disease, but instead constitutes a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Molecular gene expression studies have divided breast cancer into several categories, i.e. basallike, ErbB2 enriched, normal breast-like (adipose tissue gene signature), luminal subtype A, luminal subtype B, and claudin-low. Chances are that as our knowledge increases, each of these types will also be subclassified. More than 66% of breast carcinomas express estrogen receptor alpha (ERa) and respond to antiestrogen therapies. Most of these ERC tumors also express progesterone receptors (PRs), the expression of which has been considered as a reliable marker of a functional ER. In this paper we will review the evidence suggesting that PRs are valid targets for breast cancer therapy. Experimental data suggest that both PR isoforms (A and B) have different roles in breast cancer cell growth, and antiprogestins have already been clinically used in patients who have failed to other therapies. We hypothesize that antiprogestin therapy may be suitable for patients with high levels of PR-A. This paper will go over the experimental evidence of our laboratory and others supporting the use of antiprogestins in selected breast cancer patients.

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Differences in the binding mechanism of RU486 and progesterone to the progesterone receptor

Cited by 31 publications

References 24 publications

The negative feedback actions of progesterone on gonadotropinreleasing hormone secretion are transduced by the classical progesterone receptor

The negative feedback actions of progesterone on gonadotropinreleasing hormone secretion are transduced by the classical progesterone receptor

Modulation of Coactivator Recruitment by Cooperative Ligand Binding to Human Estrogen Receptor .ALPHA. and .BETA.

Antiprogestins in breast cancer treatment: are we ready?

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