scholarly journals A Structural and in Vitro Characterization of Asoprisnil: A Selective Progesterone Receptor Modulator

2007 ◽  
Vol 21 (5) ◽  
pp. 1066-1081 ◽  
Author(s):  
Kevin P. Madauss ◽  
Eugene T. Grygielko ◽  
Su-Jun Deng ◽  
Anthony C. Sulpizio ◽  
Thomas B. Stanley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progesterone Receptor ◽  
Crystal Structures ◽  
Nuclear Receptor ◽  
Estrogenic Activity ◽  
Uterine Fibroids ◽  
T47d Cell ◽  
Gynecological Disorders ◽  
Receptor Modulator

Abstract Selective progesterone receptor modulators (SPRMs) have been suggested as therapeutic agents for treatment of gynecological disorders. One such SPRM, asoprisnil, was recently in clinical trials for treatment of uterine fibroids and endometriosis. We present the crystal structures of progesterone receptor (PR) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor (NCoR) and SMRT. This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors. These structures show PR in a different conformation than PR complexed with progesterone (P4). We profiled asoprisnil in PR-dependent assays to understand further the PR-mediated mechanism of action. We confirmed previous findings that asoprisnil demonstrated antagonism, but not agonism, in a PR-B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay. Asoprisnil, but not RU486, weakly recruited the coactivators SRC-1 and AIB1. However, asoprisnil strongly recruited the corepressor NCoR in a manner similar to RU486. Unlike RU486, NCoR binding to asoprisnil-bound PR could be displaced with equal affinity by NCoR or TIF2 peptides. We further showed that it weakly activated T47D cell gene expression of Sgk-1 and PPL and antagonized P4-induced expression of both genes. In rat leiomyoma ELT3 cells, asoprisnil demonstrated partial P4-like inhibition of cyclooxygenase (COX) enzymatic activity and COX-2 gene expression. In the rat uterotrophic assay, asoprisnil demonstrated no P4-like ability to oppose estrogen. Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to RU486 or P4, and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus.

scholarly journals Predictive Factors of Response to Selective Progesterone Receptor Modulator (Ulipristal Acetate) in the Pharmacological Treatment of Uterine Fibroids

2020 ◽  
Vol 17 (3) ◽  
pp. 798
Author(s):  
Iwona Szydłowska ◽  
Aleksandra Marciniak ◽  
Jolanta Nawrocka-Rutkowska ◽  
Aleksandra Rył ◽  
Andrzej Starczewski
Keyword(s):  
Blood Flow ◽  
Progesterone Receptor ◽  
Predictive Factors ◽  
Uterine Fibroids ◽  
Volume Number ◽  
Ulipristal Acetate ◽  
Uterine Arteries ◽  
Receptor Modulator ◽  
Estradiol Concentration ◽  
Status Of Women

Background: Selective progesterone receptor modulator ulipristal acetate (UPA) is a drug used in management of symptomatic myomas. It was observed that the response to UPA treatment in uterine myomas varied amongst patients. An attempt was thus made at establishing predictive factors conducive to better reaction to treatment with UPA. The aim of this study was to assess the efficacy of UPA treatment in women with myomas, depending on pretreatment myomas’ volume, number of myomas, age of patients, estrogenic status of women, and pretreatment blood flow in uterine arteries. Materials and methods: The study included patients with one to four myomas. The UPA treatment was a preparation stage for surgical treatment in all patients. The study group was divided into the subgroups according to pretreatment myomas’ volume, number of myomas, age of patients, estrogenic status of women, and pretreatment blood flow in uterine arteries. Results: A better effect of reduction in size of myomas after UPA treatment was noted when pretreatment myomas’ volume was lower than 30 cm3. A significant reduction in fibroids’ size was observed after UPA therapy independently of the number of myomas and age of patients. A good response after the UPA therapy was observed when pretreatment estradiol concentration was below 50 pg/mL and when uterine artery resistance index (RI) was above 0.8. Conclusions: Our research demonstrates that treatment with ulipristal acetate is an efficient method in preoperative preparation of patients with uterine fibroids. The most important factor of positive response to UPA therapy is myoma volume. The number of myomas and patient’s age do not interfere with effects of UPA therapy. Pretreatment estradiol concentration is significant, yet secondary for the effects of therapy. The UPA therapy has no impact on blood flow in the uterine arteries and no adverse influence on estradiol concentrations.

scholarly journals 17β-Hydroxysteroid Dehydrogenase Type 1, 2, 3, and 4 Expression and Enzyme Activity in Human Anterior Pituitary Adenomas

1999 ◽  
Vol 84 (4) ◽  
pp. 1340-1345
Author(s):  
V. L. Green ◽  
V. Speirs ◽  
A. M. Landolt ◽  
P. M. Foy ◽  
S. L. Atkin
Keyword(s):  
Gene Expression ◽  
Enzyme Activity ◽  
Pituitary Adenomas ◽  
Anterior Pituitary ◽  
Estrogenic Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Messenger Ribonucleic Acid ◽  
Human Anterior Pituitary

17β-Hydroxysteroid dehydrogenase (17βHSD) isoforms reversibly catalyze the final step in the formation of estradiol (E2) from estrone (E1) and the formation of testosterone from androstenedione. We have investigated 17βHSD type 1, 2, 3, and 4 gene expression and 17βHSD estrogenic activity in human anterior pituitary adenomas. 17βHSD messenger ribonucleic acid (mRNA) expression was studied by RT-PCR in 42 pituitary tumors and 3 normal pituitaries, 17βHSD activity was studied in 11 tumors and 17βHSD type 1 was immunolocalized in vitro in 6 tumors. 17βHSD type 1 gene expression was detected in 34 of 42 adenomas in all tumor subtypes; 17βHSD type 2 mRNA was detected in 18 of 42 adenomas, but not in prolactinomas; 17βHSD type 3 mRNA was detected in 12 of 42 adenomas, but not in corticotropinomas; 17βHSD type 4 was expressed in 20 of 42 adenomas by all adenoma subtypes. Reversible 17βHSD activity was found in 9 of 11 adenomas, and 17βHSD type 1 immunopositivity was cytoplasmically distributed in all 6 adenomas in vitro. All 4 17βHSD isoforms are variably expressed in human anterior pituitary adenomas, which also show 17βHSD enzyme activity, suggesting that 17βHSD may play an important role in regulating the local cellular levels of estradiol.

scholarly journals Yeast Coactivator MBF1 Mediates GCN4-Dependent Transcriptional Activation

1998 ◽  
Vol 18 (9) ◽  
pp. 4971-4976 ◽  
Author(s):  
Ken-ichi Takemaru ◽  
Satoshi Harashima ◽  
Hitoshi Ueda ◽  
Susumu Hirose
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Dna Binding ◽  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Crucial Role ◽  
Tata Binding Protein ◽  
Binding Region

ABSTRACT Transcriptional coactivators play a crucial role in gene expression by communicating between regulatory factors and the basal transcription machinery. The coactivator multiprotein bridging factor 1 (MBF1) was originally identified as a bridging molecule that connects theDrosophila nuclear receptor FTZ-F1 and TATA-binding protein (TBP). The MBF1 sequence is highly conserved across species fromSaccharomyces cerevisiae to human. Here we provide evidence acquired in vitro and in vivo that yeast MBF1 mediates GCN4-dependent transcriptional activation by bridging the DNA-binding region of GCN4 and TBP. These findings indicate that the coactivator MBF1 functions by recruiting TBP to promoters where DNA-binding regulators are bound.

scholarly journals Markers of Inflammation and Vascular Parameters in Selective Progesterone Receptor Modulator (Ulipristal Acetate)-Treated Uterine Fibroids

2021 ◽  
Vol 10 (16) ◽  
pp. 3721
Author(s):  
Iwona Szydłowska ◽  
Marta Grabowska ◽  
Jolanta Nawrocka-Rutkowska ◽  
Andrzej Kram ◽  
Małgorzata Piasecka ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Inflammatory Markers ◽  
Uterine Fibroids ◽  
Response To Treatment ◽  
Control Group ◽  
Ulipristal Acetate ◽  
Weak Response ◽  
Receptor Modulator ◽  
Markers Of Inflammation ◽  
Response Group

The exact mechanism of selective progesterone receptor modulator action in leiomyoma still challenges researchers. The aim of the study was to assess the effects of ulipristal acetate (UPA) on immunoexpression of inflammatory markers and vascularization in fibroids. UPA-treated patients were divided into three groups: (1) good response (≥25% reduction in volume of fibroid), (2) weak response (insignificant volume reduction), (3) and no response to treatment (no decrease or increase in fibroid volume). The percentage of TGFβ, IL6, IL10, CD117, and CD68-positive cells were significantly lower in the group with a good response to treatment vs. the control group. Moreover, the percentage of IL10 and CD68-positive cells in the group with a good response to treatment were also significantly lower compared to the no response group. Additionally, a significant decrease in the percentage of IL10-positive cells was found in the good response group vs. the weak response group. There were no statistical differences in the percentage of TNFα-positive cells and vessel parameters between all compared groups. The results of the study indicate that a good response to UPA treatment may be associated with a decrease of inflammatory markers, but it does not influence myoma vascularization.

scholarly journals Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice

2020 ◽  
Vol 21 (19) ◽  
pp. 7148
Author(s):  
Kamalakannan Radhakrishnan ◽  
Yong-Hoon Kim ◽  
Yoon Seok Jung ◽  
Jina Kim ◽  
Don-Kyu Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Molecular Mechanism ◽  
Nuclear Receptor ◽  
Iron Homeostasis ◽  
Luciferase Reporter ◽  
Orphan Nuclear Receptor ◽  
Knock Out

Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, but would be of great help to externally modulate iron load in pathologic conditions. Here, we describe a detailed molecular mechanism of hepatic BMP6 gene expression by an orphan nuclear receptor, estrogen-related receptor γ (ERRγ), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRγ and BMP6 expression. Overexpression of ERRγ is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRγ. In line, knock-down of ERRγ in cell lines or a hepatocyte specific knock-out of ERRγ in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRγ directly binds to the ERR response element (ERRE) in the mouse BMP6 gene promoter and positively regulates BMP6 gene transcription in IL-6 treatment conditions, which is further confirmed by ERRE mutated mBMP6-luciferase reporter assays. Finally, an inverse agonist of ERRγ, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRγ mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6.

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