Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We studied the effects of 17beta-estradiol, progesterone, and dihydrotestosterone on in vitro growth of human metastatic melanoma. Each sex hormone inhibited the growth of melanoma receptor-dependently; 17beta-estradiol inhibited 3H-thymidine uptake of estrogen receptor-positive WM266-4 and NM26, but not that of the receptor-negative HS15. Progesterone inhibited 3H-thymidine uptake of progesterone receptor-positive WM266-4 and HS15, but not that of the receptor-negative NM26. Dihydrotestosterone inhibited 3H-thymidine uptake of androgen receptor-positive HS15 and NM26, but not that of the receptor-negative WM266-4. The growth inhibition by each hormone was counteracted by the respective hormone receptor antagonist. The combination of more than two hormones neither gave additive nor synergistic growth inhibition. The growth inhibition by each sex hormone was counteracted by interleukin-8 but not by the other growth factors. Each sex hormone reduced the constitutive interleukin-8 secretion and mRNA levels in the respective receptor-positive melanoma but not in the receptor-negative melanoma. Transient transfection showed that each sex hormone inhibited the constitutive chloramphenicol acetyltransferase expression driven by interleukin-8 promoter in the respective receptor-positive melanoma but not in the receptor-negative melanoma. Transfection with a series of 5'-deleted interleukin-8 promoter/chloramphenicol acetyltransferase reporter constructs demonstrated that the sequences between -98 and -63 bp on interleukin-8 promoter may be involved in the transcriptional repression. These data suggest that 17beta-estradiol, progesterone, and dihydrotestosterone suppress the growth of melanoma by inhibiting interleukin-8 production in a receptor-dependent manner.
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PMID:17beta-estradiol, progesterone, and dihydrotestosterone suppress the growth of human melanoma by inhibiting interleukin-8 production. 1151 5

The present study addresses the capacity of heregulin (HRG), a ligand of type I receptor tyrosine kinases, to transactivate the progesterone receptor (PR). For this purpose, we studied, on the one hand, an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female BALB/c mice and, on the other hand, the human breast cancer cell line T47D. HRG was able to exquisitely regulate biochemical attributes of PR in a way that mimicked PR activation by progestins. Thus, HRG treatment of primary cultures of epithelial cells of the progestin-dependent C4HD murine mammary tumor line and of T47D cells induced a decrease of protein levels of PRA and -B isoforms and the downregulation of progesterone-binding sites. HRG also promoted a significant increase in the percentage of PR localized in the nucleus in both cell types. DNA mobility shift assay revealed that HRG was able to induce PR binding to a progesterone response element (PRE) in C4HD and T47D cells. Transient transfections of C4HD and T47D cells with a plasmid containing a PRE upstream of a chloramphenicol acetyltransferase (CAT) gene demonstrated that HRG promoted a significant increase in CAT activity. In order to assess the molecular mechanisms underlying PR transactivation by HRG, we blocked ErbB-2 expression in C4HD and T47D cells by using antisense oligodeoxynucleotides to ErbB-2 mRNA, which resulted in the abolishment of HRG's capacity to induce PR binding to a PRE, as well as CAT activity in the transient-transfection assays. Although the inhibition of HRG binding to ErbB-3 by an anti-ErbB-3 monoclonal antibody suppressed HRG-induced PR activation, the abolishment of HRG binding to ErbB-4 had no effect on HRG activation of PR. To investigate the role of mitogen-activated protein kinases (MAPKs), we used the selective MEK1/MAPK inhibitor PD98059. Blockage of MAPK activation resulted in complete abrogation of HRG's capacity to induce PR binding to a PRE, as well as CAT activity. Finally, we demonstrate here for the first time that HRG-activated MAPK can phosphorylate both human and mouse PR in vitro.
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PMID:Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells. 1252 13

The ability of metals to activate estrogen receptor-alpha (ERalpha) was measured in the human breast cancer cell line, MCF-7. Similar to estradiol, treatment of cells with the divalent metals copper, cobalt, nickel, lead, mercury, tin, and chromium or with the metal anion vanadate stimulated cell proliferation; by d 6, there was a 2- to 5-fold increase in cell number. The metals also decreased the concentration of ERalpha protein and mRNA by 40-60% and induced expression of the estrogen-regulated genes progesterone receptor and pS2 by1.6- to 4-fold. Furthermore, there was a 2- to 4-fold increase in chloramphenicol acetyltransferase activity after treatment with the metals in COS-1 cells transiently cotransfected with the wild-type receptor and an estrogen-responsive chloramphenicol acetyltransferase reporter gene. The ability of the metals to alter gene expression was blocked by an antiestrogen, suggesting that the activity of these compounds is mediated by ERalpha. In binding assays the metals blocked the binding of estradiol to the receptor without altering the apparent binding affinity of the hormone (K(d) = 10(-10) M). Scatchard analysis employing either recombinant ERalpha or extracts from MCF-7 cells demonstrated that (57)Co and (63)Ni bind to ERalpha with equilibrium dissociation constants of 3 and 9.5 x 10(-9) and 2 and 7 x 10(-9) M, respectively. The ability of the metals to activate a chimeric receptor containing the hormone-binding domain of ERalpha suggests that their effects are mediated through the hormone-binding domain. Mutational analysis identified amino acids C381, C447, E523, H524, N532, and D538 as potential interaction sites, suggesting that divalent metals and metal anions activate ERalpha through the formation of a complex within the hormone-binding domain of the receptor.
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PMID:Estrogen-like activity of metals in MCF-7 breast cancer cells. 1274 4

It is well established that steroid receptor function requires interaction with coactivators. However, the mechanisms through which steroid receptors elicit precise assembly of coactivator complexes and the way the steroid activation signal is transduced remain elusive. Using a T47D cell line stably integrated with a mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter, we demonstrate that specific steroid receptors exhibit preferential recruitment of SRC-1 family coactivators, which determines the subsequent recruitment of specific downstream coregulator molecules. Upon ligand treatment, progesterone receptor (PR) interacted preferentially with SRC-1, which recruited CBP and significantly enhanced acetylation at K5 of histone H4. In contrast, activated glucocorticoid receptor (GR) preferentially associated with SRC-2 (TIF-2/GRIP-1), which subsequently recruited pCAF and led to specific modification of histone H3, suggesting that specific coactivators recruit distinct histone acetyltransferases to modulate the transcription of steroid-responsive genes. Loss-of-function experiments further support the predicted roles of SRC-1 and SRC-2 in, respectively, PR- and GR-mediated transcription on the MMTV promoter. This study indicates that differential recruitment of coactivators by nuclear receptors determines the assembly of coactivator complexes on target promoters to mediate specific transcription signals.
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PMID:Progesterone and glucocorticoid receptors recruit distinct coactivator complexes and promote distinct patterns of local chromatin modification. 1274 80

The human progesterone receptor (PR) contains multiple Ser-Pro phosphorylation sites that are potential substrates for cyclin-dependent kinases, suggesting that PR activity might be regulated during the cell cycle. Using T47D breast cancer cells stably transfected with an mouse mammary tumor virus (MMTV) chloramphenicol acetyltransferase reporter (Cat0) synchronized in different phases of the cell cycle, we found that PR function and phosphorylation is remarkably cell cycle dependent, with the highest activity in S phase. Although PR expression was reduced in the G2/M phase, the activity per molecule of receptor was markedly reduced in both G1 and G2/M phases compared to the results seen with the S phase of the cell cycle. Although PR is recruited to the MMTV promoter equivalently in the G1 and S phases, recruitment of SRC-1, SRC-3, and, consequently, CBP is reduced in G1 phase despite comparable expression levels of SRC-1 and SRC-3. In G2/M phase, site-specific phosphorylation of PR at Ser162 and at Ser294, a site previously reported to be critical for transcriptional activity and receptor turnover, was abolished. Treatment with the histone deacetylase inhibitor trichostatin A elevated G1 and G2/M activity to that of the S phase, indicating that the failure to recruit sufficient levels of active histone acetyltransferase is the primary defect in PR-mediated transactivation.
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PMID:Human progesterone receptor displays cell cycle-dependent changes in transcriptional activity. 1579 79

Oestrogen, progesterone and paracrine signals from the embryo have been associated with the overall control of implantation. Changes in the expression of the heavily glycosylated transmembrane glycoprotein MUC1 mucin on the endometrial epithelium are also thought to be important for embryo attachment. Increased MUC1 expression has been correlated with elevated progesterone levels in the secretory phase of the menstrual cycle. Embryonic control of endometrial receptivity through changes in MUC1 expression could be achieved through the interleukin-1 system. Four endometrial epithelial cell lines (HEC1A, HEC1B, Ishikawa and RL592) were treated with oestrogen and progesterone (with or without interleukin-1-beta) and were subjected to immunocytochemistry and flow cytometric analysis to determine MUC1 production using MUC1 antibodies. HEC1A (oestrogen receptor (ER) and progesterone receptor (PR) positive) and HEC1B (ER positive and PR negative) were transfected with the MUC1 promoter, underwent similar treatment regimes and the activity of the MUC1 promoter relative to their untreated controls was determined using a chloramphenicol acetyltransferase (CAT) enzyme-linked immunoassay. Using the cell lines, we determined that endometrial MUC1 expression is up-regulated by progesterone, consistent with the in vivo increases in MUC1 related to high progesterone levels. We also revealed that neither oestrogen, nor interleukin-1-beta, appear to modulate MUC1. Progesterone-dependent regulation of MUC1 is likely to be an important factor in determining endometrial receptivity.
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PMID:The effects of sex steroid hormones and interleukin-1-beta on MUC1 expression in endometrial epithelial cell lines. 1659 24


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