Steroid receptor dna binding

Sex hormone-binding globulin (SHBG) is thought to mainly function as a transporter and reservoir for the estradiol and testosterone sex hormones. However it has also been demonstrated that SHBG can bind to a cell surface receptor (SHBG-R). The SHBG-R has not been completely characterized. A subset of steroids are able to bind to the SHBG/SHBG-R complex resulting in an activation of adenylyl cyclase and synthesis of the cAMP second messenger. [19] Hence the SHBG/SHBG-R complex appears to act as a transmembrane steroid receptor that is capable of transmitting signals to the interior of cells.

Mitogenic function of E-ER relies on the presence of sufficient supply of nutrients such as glucose, because E-ER signaling also promotes the glycolysis and Krebs cycling [ 75 ]. A recent work, however, reported that estrogen up-regulates glycolysis via activation of PI3K-AKT signaling pathway, promotes cell proliferation under high glucose condition and represses Krebs cycle simultaneously [ 76 , 77 ]. This is similar to the situation in proliferating cancer cells that consume glucose and rely on glycolysis over Krebs cycle in generating ATP, which is termed as “Warburg effect” [ 78 ]. However, when the extracellular glucose decreases, estrogen treatment activates mitochondria respiration via up-regulating PDH (pyruvate dehydrogenase) activity and repressing glycolysis [ 76 ], suggesting estrogen's effect on cell metabolism is adaptable and is under control of glucose availability. In the scenarios of cancer prone condition, glucose is frequently enriched. Estrogen probably promotes the cell proliferation by stimulating the anabolic metabolism. In fact, release of glycolysis proteins into plasma precedes the diagnosis of ER + breast carcinoma [ 79 ], suggesting E-ER signaling promoted glycolysis is a very early event that associates with tumorigenesis. It was shown that the genes maximally induced by estrogen treatment after relatively long time (160 mins) incubation have the top hit of GO (gene ontology) term “cellular biosynthetic process” by ontology analysis [ 67 ]. These observations indicate E-ER signaling plays an important role in promoting tumor growth. But the E-ER signaling may also have its own risk management strategy because BRCA1 is responsive to E-ER signaling, and the response of BRCA1 needs to be mediated by CtBP and the cell metabolite NADH [ 65 ]. Estrogen was found to be able to activate tumor suppressor gene expression via manipulation of the cellular metabolism status globally [ 65 ]. Although BRCA1 function in regulating cell metabolism pathways has just been realized, several recent findings suggested that BRCA1 is a negative regulator of anabolic cell metabolism. BRCA1 has been shown to negatively regulate Igf-1 expression and mediate phosphorylated AKT degradation [ 80 , 81 ]. Also, BRCA1 directly inhibits ACC (acetyl-CoA carboxylase) by interacting with it [ 82 ]. ACC catalyzes the converting of Acetyl-CoA to malonyl-CoA during fatty acid synthesis which is essential for tumor cell growth [ 83 ]. Since de novo fatty acid synthesis frequently associates with cancer cell growth, and probably the EMT, it suggests BRCA1 has novel tumor repressor function by controlling fatty acids metabolism. Thus, E-ER activated BRCA1 expression forms an important negative regulatory feedback that slows down the anabolic process promoted by E-ER.

ARN-509 (< 10 μM) inhibits androgen-mediated induction or repression of mRNA expression levels for 13 endogenous genes including PSA and TMPRSS2 in the LNCaP/AR prostate cancer cell line. ARN-509 (< 10 μM) inhibits the proliferative effect of R1881 (30 pM) in the LNCaP/AR prostate cancer cell line. ARN-509 (10 μM) impairs AR nuclear localization and thus reduces the concentration of AR available to bind androgen response elements (ARE) in LNCaP cells expressing AR-EYFP. ARN-509 (10 μM) is able to effectively compete with R1881 (1 nM) and prevent AR from binding to promoter regions. ARN-509 inhibits R1881-induced VP16-AR–mediated transcription with IC50 of μM in Hep-G2 cells expressing a VP16-AR fusion protein and an ARE-driven luciferase reporter. [1]

ONC1-0013B inhibits AR activity in vitro. A. ONC1-0013B structure. B. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 1 day. PSA expression plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). Ki values: ± (ONC1-13B), ± (MDV3100), (ARN-509). Mean±SEM from 5 replicate experiments (except ARN-509). C. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 5 days. Viable cells plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). IC50 values: 30nM (ONC1-13B), 148nM (MDV3100), 240nM (ARN-509). D. Competitive-binding assay vs AR ligand Fluormone™ (PolarScreen™ Androgen Receptor Competitor Assay). IC50 values: 19nM (DHT), (ONC1-13B), (MDV3100).

As demonstrated in progesterone receptor-deficient mice, the physiological effects of progesterone depend completely on the presence of the human progesterone receptor (hPR), a member of the steroid-receptor superfamily of nuclear receptors. The single-copy human (hPR) gene uses separate promoters and translational start sites to produce two isoforms, hPR-A and -B, which are identical except for an additional 165 amino acids present only in the N terminus of hPR-B. [12] Although hPR-B shares many important structural domains with hPR-A, they are in fact two functionally distinct transcription factors, mediating their own response genes and physiological effects with little overlap. Selective ablation of PR-A in a mouse model, resulting in exclusive production of PR-B, unexpectedly revealed that PR-B contributes to, rather than inhibits, epithelial cell proliferation both in response to estrogen alone and in the presence of progesterone and estrogen. These results suggest that in the uterus, the PR-A isoform is necessary to oppose estrogen-induced proliferation as well as PR-B-dependent proliferation.

Steroid receptor dna binding

steroid receptor dna binding

ONC1-0013B inhibits AR activity in vitro. A. ONC1-0013B structure. B. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 1 day. PSA expression plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). Ki values: ± (ONC1-13B), ± (MDV3100), (ARN-509). Mean±SEM from 5 replicate experiments (except ARN-509). C. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 5 days. Viable cells plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). IC50 values: 30nM (ONC1-13B), 148nM (MDV3100), 240nM (ARN-509). D. Competitive-binding assay vs AR ligand Fluormone™ (PolarScreen™ Androgen Receptor Competitor Assay). IC50 values: 19nM (DHT), (ONC1-13B), (MDV3100).

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