Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.28 (chloramphenicol acetyltransferase)
 5,100 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In most cells and tissues containing androgen receptors (ARs), androgen regulates the levels of AR messenger RNA (mRNA). As the AR concentration is correlated with androgen responsiveness, this autoregulation of AR mRNA may affect cellular sensitivity to androgens. Androgens decrease levels of AR mRNA in many cell lines and tissues; however, in some tissues and possibly also at certain developmental stages, AR mRNA is up-regulated by androgens. Sequences within the 5'-flanking region and AR promoter do not appear to be sufficient for androgen regulation of AR mRNA. We have previously shown that both down- and up-regulation of AR mRNA by androgen can be reproduced in cell lines expressing a transfected human AR complementary DNA (cDNA). Sequences within the AR cDNA confer this autoregulation in transfected cells, suggesting that sequences within the transcribed region of the AR gene are sufficient for autoregulation. In this study we have determined the mechanism of androgenic up-regulation of AR mRNA encoded by the human AR cDNA in the prostate cancer cell line, PC3, and have identified the cis-acting sequences of the AR cDNA that are required. The observations that actinomycin D blocked androgenic up-regulation of AR mRNA but cycloheximide had no effect are consistent with a model in which AR is directly involved in transcriptional up-regulation of AR cDNA expression. Nuclear run-on assays showed that androgen treatment resulted in increased transcription of the AR cDNA. Furthermore, a 350-bp AR cDNA fragment inserted 5' of a thymidine kinase promoter-chloramphenicol acetyltransferase gene conferred androgen induction of chloramphenicol acetyltransferase activity in PC3 cells. This 350-bp fragment, which is located in the AR coding region, contains two putative androgen response elements (AREs) separated by 182 bp. The 5'-most ARE (ARE-1, 5'-TGTCCT-3') resembles a half-site of the palindromic consensus hormone response element, recognized by several steroid receptors, including AR, and the 3'-sequence (ARE-2, 5'-AGTACTCC-3') is identical to a portion of an androgen-responsive region found in the rat probasin gene promoter. Analysis of either ARE-1 or ARE-2 mutants revealed that these elements function synergistically. AR protein binds to the 350-bp fragment, as demonstrated by electrophoretic mobility shift assays using a glutathione-S-transferase-AR fusion protein containing the DNA- and steroid-binding domains of AR. These results indicate that the AR coding region contains an androgen-responsive region that is involved in cell line-specific up-regulation of AR mRNA.
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PMID:Two androgen response elements in the androgen receptor coding region are required for cell-specific up-regulation of receptor messenger RNA. 896 Dec 68

The Nrf2 (nuclear factor-erythroid 2 p45-related factor 2) transcription factor regulates gene expression of the GCLC (glutamate-cysteine ligase catalytic subunit), which is a key enzyme in glutathione synthesis, and GSTs (glutathione S-transferases) via the ARE (antioxidant-response element). The Mrp2 (multidrug-resistance protein 2) pump mediates the excretion of GSH and GSSG excretion as well as endo- and xeno-biotics that are conjugated with GSH, glucuronate or sulphate. Considering that Mrp2 acts synergistically with these enzymes, we hypothesized that the regulation of Mrp2 gene expression is also dependent on Nrf2. Using BHA (butylated hydroxyanisole), which is a classical activator of the ARE-Nrf2 pathway, we observed an increase in the transcriptional activity of Mrp2, GCLC and Gsta1/Gsta2 genes in the mouse liver. A similar pattern of co-induction of Mrp2 and GCLC genes was also observed in mouse (Hepa 1-6) and human (HepG2) hepatoma cells treated with BHA, beta-NF (beta-naphthoflavone), 2,4,5-T (trichlorophenoxyacetic acid) or 2AAF (2-acetylaminofluorene), suggesting that these genes share common mechanism(s) of transcriptional activation in response to exposure to xenobiotics. To define the mechanism of Mrp2 gene induction, the 5'-flanking region of the mouse Mrp2 gene (2.0 kb) was isolated, and two ARE-like sequences were found: ARE-2 (-1391 to -1381) and ARE-1 (-95 to -85). Deletion analyses demonstrated that the proximal region (-185 to +99) contains the elements for the basal expression and xenobiotic-mediated induction of the Mrp2 gene. Gel-shift and supershift assays indicated that Nrf2-protein complexes bind ARE sequences of the Mrp2 promoter, preferentially to the ARE-1 sequence. Overexpression of Nrf2 increased ARE-1-mediated CAT (chloramphenicol acetyltransferase) gene activity, while overexpression of mutant Nrf2 protein repressed the activity. Thus Nrf2 appears to regulate Mrp2 gene expression via an ARE element located at the proximal region of its promoter in response to exposure to xenobiotics.
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PMID:Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. 1642 33