Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human progesterone receptor (PR) exists as two functionally distinct isoforms, hPRA and hPRB. hPRB functions as a transcriptional activator in most cell and promoter contexts, while hPRA is transcriptionally inactive and functions as a strong ligand-dependent transdominant repressor of steroid hormone receptor transcriptional activity. Although the precise mechanism of hPRA-mediated transrepression is not fully understood, an inhibitory domain (ID) within human PR, which is necessary for transrepression by hPRA, has been identified. Interestingly, although ID is present within both hPR isoforms, it is functionally active only in the context of hPRA, suggesting that the two receptors adopt distinct conformations within the cell which allow hPRA to interact with a set of cofactors that are different from those recognized by hPRB. In support of this hypothesis, we identified, using phage display technology, hPRA-selective peptides which differentially modulate hPRA and hPRB transcriptional activity. Furthermore, using a combination of in vitro and in vivo methodologies, we demonstrate that the two receptors exhibit different cofactor interactions. Specifically, it was determined that hPRA has a higher affinity for the corepressor SMRT than hPRB and that this interaction is facilitated by ID. Interestingly, inhibition of SMRT activity, by either a dominant negative mutant (C'SMRT) or histone deacetylase inhibitors, reverses hPRA-mediated transrepression but does not convert hPRA to a transcriptional activator. Together, these data indicate that the ability of hPRA to transrepress steroid hormone receptor transcriptional activity and its inability to activate progesterone-responsive promoters occur by distinct mechanisms. To this effect, we observed that hPRA, unlike hPRB, was unable to efficiently recruit the transcriptional coactivators GRIP1 and SRC-1 upon agonist binding. Thus, although both receptors contain sequences within their ligand-binding domains known to be required for coactivator binding, the ability of PR to interact with cofactors in a productive manner is regulated by sequences contained within the amino terminus of the receptors. We propose, therefore, that hPRA is transcriptionally inactive due to its inability to efficiently recruit coactivators. Furthermore, our experiments indicate that hPRA interacts efficiently with the corepressor SMRT and that this activity permits it to function as a transdominant repressor.
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PMID:The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. 1075 95

Progesterone participates in the regulation of several physiological processes in mammals. The biological response to progesterone is mediated by two forms of the progesterone receptor (PR) denominated PR-A and PR-B. The difference between them is that 164 amino acids of N-terminal of PR-B are absent in PR-A. Both PR isoforms are derived from a single gene but are generated from either alternative transcriptional or translational start sites, and are regulated by different estrogen-induced promoters. PR-B acts as a transcriptional activator in different cellular contexts whereas PR-A functions as a strong inhibitor of transcriptional activity. PR isoforms expression and function vary among target tissues such as the uterus, the mammary gland and the brain. The knowledge of the molecular mechanisms involved in the regulation of expression and function of PR isoforms will contribute to the understanding of fundamental biological processes such as sexual behavior and reproduction, and it will open the possibility of alternative therapies in fertility control as well as in the treatment of breast, endometrial and cerebral tumors.
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PMID:[Progesterone receptor isoforms: function and regulation]. 1125 12

GATA binding protein 3 (GATA3) is a transcriptional activator highly expressed by the luminal epithelial cells in the breast. Here we did a meta-analysis of the available breast cancer cDNA data sets on a cohort of 305 patients and found that GATA3 was one of the top genes with low expression in invasive carcinomas with poor clinical outcome. To validate its prognostic utility, we did a tissue microarray analysis on a cohort of 139 consecutive invasive carcinomas (n = 417 tissue samples) immunostained with a monoclonal antibody against GATA3. Low GATA3 expression was associated with higher histologic grade (P < 0.001), positive nodes (P = 0.002), larger tumor size (P = 0.03), negative estrogen receptor and progesterone receptor (P < 0.001 for both), and HER2-neu overexpression (P = 0.03). Patients whose tumors expressed low GATA3 had significantly shorter overall and disease-free survival when compared with those whose tumors had high GATA3 levels. The hazard ratio of metastasis or recurrence according to the GATA3 status was 0.31 (95% confidence interval, 0.13-0.74; P = 0.009). Cox multivariate analysis showed that GATA3 had independent prognostic significance above and beyond conventional variables. Our data suggest that immunohistochemical analysis of GATA3 may be the basis for a new clinically applicable test to predict tumor recurrence early in the progression of breast cancer.
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PMID:Identification of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis. 1635 29

Progesterone is known to be metabolized into various metabolites exerting various effects, predominantly into 5alpha-pregnanes and 4-pregnenes. Studies on uterine tissues showed numerous progesterone-converting enzymes such as 5alpha-reductase (5alphaR), 5beta-reductase, 3alpha-, 3beta-, 20alpha-, and 20beta-hydroxysteroid oxidoreductases and others. The main progesterone-metabolizing enzymes in human breast tissues are 5alphaR, 3alpha-HSO 3beta-HSO, and 20alpha-HSO. Tumor genesis in the breast has been shown to be enhanced by high 5alphaR activity and suppression of 3alpha-HSO and 20alpha-HSO. A major determinant of 5alphaR, the breast's gate-keeping enzyme activity is the genetic variation in the enzyme's gene. Two polymorphisms within the steroid 5alphaR type 2 gene, Ala>Thr at codon 49 and Val>Leu at codon 89 have been reported to strongly affect the enzyme's activity, even in regard to breast cancer risk. As steroid hormones are known to be converted into many other steroids occupying different receptors and thereby exerting various different effects, progesterone receptors are important factors when mediating the hormone's effects. The progesterone receptor (PR) gene is transcribed from one gene by two alternative promoters and translated into PR-B, a potent transcriptional activator, and PR-A, the shorter isoform, necessary to oppose the effects of PR-B. In addition, endocrine reactions are modulated by epigenetics. The expression of progesterone receptors has been shown to be up- and downregulated by various epigenetic mechanisms. Many factors must be also taken into account in hormonal (replacement) therapy. Thus natural steroids should not be disparaged as treatment options for gender-specific diseases. An update on endocrinological knowledge and experience is rather mandatory for gynaecologists.
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PMID:The dialectic role of progesterone. 1917 45

Jun dimerization protein 2 (JDP2), a basic leucine zipper transcription factor, is involved in numerous biological and cellular processes such as cancer development and regulation, cell-cycle regulation, skeletal muscle and osteoclast differentiation, progesterone receptor signaling, and antibacterial immunity. Though JDP2 is widely expressed in mammalian tissues, its function in gonads and adrenals (such as regulation of steroidogenesis and adrenal development) is largely unknown. Herein, we find that JDP2 mRNA and proteins are expressed in mouse adrenal gland tissues. Moreover, overexpression of JDP2 in Y1 mouse adrenocortical cancer cells increases the level of melanocortin 2 receptor (MC2R) protein. Notably, Mc2r promoter activity is activated by JDP2 in a dose-dependent manner. Next, by mapping the Mc2r promoter, we show that cAMP response elements (between -1320 and -720-bp) are mainly required for Mc2r activation by JDP2 and demonstrate that -830-bp is the major JDP2 binding site by real-time chromatin immunoprecipitation (ChIP) analysis. Mutations of cAMP response elements on Mc2r promoter disrupts JDP2 effect. Furthermore, we demonstrate that removal of phosphorylation of JDP2 results in attenuated transcriptional activity of Mc2r. Finally, we show that JDP2 is a candidate for SUMOylation and SUMOylation affects JDP2-mediated Mc2r transcriptional activity. Taken together, JDP2 acts as a novel transcriptional activator of the mouse Mc2r gene, suggesting that JDP2 may have physiological functions as a novel player in MC2R-mediated steroidogenesis as well as cell signaling in adrenal glands.
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PMID:Jun Dimerization Protein 2 Activates Mc2r Transcriptional Activity: Role of Phosphorylation and SUMOylation. 2814 18

Eyes absent homolog 2 (EYA2), a transcriptional activator, is pivotal for organ development, but aberrant regulation of EYA2 has been reported in multiple human tumors. However, the role of EYA2 in breast cancer is still lack of full understanding. To explore the biological significance of EYA2 in breast cancer, we conducted data analysis on public breast cancer datasets, and performed immunohistochemistry (IHC) analysis, colony-forming unit assays, EdU assay, western blotting, and immunofluorescence (IF). Meta-analysis showed that EYA2 mRNA expression was correlated with tumor grade, the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). IHC analysis displayed that EYA2 protein abundance was inversely associated with the status of ER and PR, and enriched in triple-negative breast cancer in comparison with luminal-type tumors. Additionally, correlation analysis reflected that EYA2 mRNA was negatively correlated with luminal markers, and positively associated with markers of basal cells, epithelial-mesenchymal transition and cancer stem cells. Clone-forming assay and EdU experiment showed that EYA2 overexpression enhanced proliferation of breast cancer cells. Results from western blotting and IF displayed that overexpression of EYA2 up-regulated the protein abundance of proliferation markers. Importantly, survival analysis indicated that higher EYA2 mRNA level predicted worse overall survival, relapse-free survival and metastasis-free survival among whole enrolled breast cancer patients. Collectively, EYA2 was closely correlated with clinico-pathological characteristics, and served as a proliferation stimulator for breast cancer cells and an unfavorable prognostic element for breast cancer patients, suggesting that EYA2 is involved in the progression of breast carcinoma.
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PMID:EYA2 Correlates With Clinico-Pathological Features of Breast Cancer, Promotes Tumor Proliferation, and Predicts Poor Survival. 3076 Dec 70


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