Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have employed a yeast (Saccharomyces cerevisiae) based rat androgen receptor expression system to examine the cross-talk between different signalling pathways. We report here the synergistic modulation of androgen regulated transcriptional activation of beta-galactosidase reporter activity by the activators of protein kinase-A, like forskolin and 8-bromo-cyclic AMP. A similar ligand-dependent enhancement of reporter activity compared to a DHT treated control has been noticed with okadaic acid, which is a potent inhibitor of protein phosphatase. The activation could be blocked by protein kinase-A/C inhibitor, H7. Forskolin treatment neither altered levels of receptor mRNA nor [3H]R1881 binding to the receptor. Although it promotes binding of receptor to an androgen response element, forskolin was unable to activate subsequent interaction with the transcription machinery in the absence of androgen. Additionally, the synergistic actions of these activators were independent of the degree of androgen response element occupancy. Anti-androgens, cyproterone acetate and flutamide, which failed to exhibit antagonistic behaviour with yeast expressed receptor, were able to antagonize only the forskolin mediated augmentation of reporter activity. Finally, analyses of mutants established the role of DNA and steroid binding domains of receptor for this synergism.
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PMID:Synergistic activation of yeast-expressed rat androgen receptor by modulators of protein kinase-A. 1002 42

Serum apolipoprotein AI (apoAI) levels correlate with the risk of developing atherosclerosis. Previous studies have suggested that dehydroepiandrosterone (DHEA) lowers high-density lipoprotein (HDL)-cholesterol levels. We investigated whether or not DHEA may lower HDL-cholesterol levels by suppressing apoAI gene transcription in hepatocytes. ApoAI mRNA levels, assessed by Northern blotting, were suppressed in HepG2 cells treated with DHEA (34%) (10 microg/mL) or testosterone (36%) (T, 1 microg/mL). Estradiol alone (E2, 1 microg/mL) had relatively little effect on apoAI mRNA levels, while E2 in combination with DHEA prevented a decrease in apoAI mRNA levels compared to DHEA alone. To determine whether these effects were due to changes in apoAI gene transcription, HepG2 cells were transfected with a plasmid carrying the full-length promoter of the rat apoAI gene ligated into a chloramphenicol acetyltransferase (CAT) reporter construct. The plasmid pCMV.SPORT-beta-gal was included in each transfection to normalize the data to transfection efficiency. Cells were then cultured in the presence or absence of DHEA (10 microg/mL), T (1 microg/mL), 17alpha-methyltestosterone (MTT, 1 microg/mL), 5alpha-dihydrotestosterone (DHT, 1 microg/mL), E2 (1 microg/mL), or a combination of DHEA plus E2, T plus E2, MTT plus E2, and DHT plus E2, for 24 hours. CAT activity, relative to beta-galactosidase activity, was reduced by 19.6%, 57.6%, 38.6%, and 54.6% with DHEA, T, DHT, and MTT addition, respectively. E2 increased CAT activity by 43.8%. When the androgens (ie, DHEA, T, DHT, or MTT) were combined with E2, apoAI promoter activity was suppressed. We conclude, therefore, that androgens downregulate apoAI promoter activity in the presence or absence of E2. However, the changes in mRNA levels do not always reflect changes in promoter activity, suggesting that these steroids may have additional post-transcriptional effects on steady-state apoAI mRNA levels. It remains to be established if the transcriptional effects we observed are mediated through an androgen response element.
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PMID:Effects of dehydroepiandrosterone on rat apolipoprotein AI gene expression in the human hepatoma cell line, HepG2. 1188 77

Anti-convulsant treatment is associated with a high prevalence of reproductive dysfunction compared with age-matched non-epileptics. We examined the widely used anti-convulsants valproate (VPA) and carbamazepine (CBZ) for steroidal bioactivity using a yeast-based steroid receptor-beta-galactosidase reporter assay for the androgen receptor (AR), progesterone receptor (PR) or estrogen receptor (ER). Bioassays were performed (a) to detect agonist activity by exposing yeast to 100 microM CBZ or VPA or (b) to detect antagonist activity by exposing yeast stimulated with testosterone (5 x 10(-9) M, AR), progesterone (1.6 x 10(-9) M, PR) or estradiol (2.6 x 10(-11) M, ER) together with either VPA or CBZ for 4 (PR) or 16 (AR, ER) hours. VPA showed dose-dependent (1-800 microM) inhibition of progesterone-induced PR- and testosterone-induced AR activity but had no ER antagonist bioactivity and no significant PR, AR or ER agonist bioactivity. VPA also showed a dose-dependent (1-200 microM) blockade of DHT's suppression of AR-mediated NF-kappaB activation in human mammalian cells. By contrast, CBZ had no significant PR, AR or ER agonist or AR and ER antagonist bioactivity but at the highest concentration tested (800 microM) it did antagonize PR activity. We conclude that VPA is a non-steroidal antagonist for human AR and PR but not ER. VPA's androgen and progesterone antagonism at concentrations within therapeutic blood levels (350-700 microM) seems likely to contribute to the frequency of reproductive endocrine disturbances among patients treated with VPA.
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PMID:Valproate is an anti-androgen and anti-progestin. 1616 77