Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) (10 nM) produce a marked reduction in the growth, measured by thymidine uptake, of MCF-7 cells in full growth medium, but had only a small effect on MDA-MB-231 and T47D cells. Bryostatin alone also inhibited growth but to a lesser extent than seen with TPA. The effect of TPA on MCF-7 cells was partially reversed by bryostatin, added simultaneously or after TPA, suggesting bryostatin does not simply mimic TPA in this system. Even though both are believed to act via effects on protein kinase C, bryostatin appears to act as antagonist to the effect of TPA as well as a partial agonist on its own. When the oestrogen receptor positive MCF-7 and T47D cells were maintained in charcoal stripped serum, the increase in DNA synthesis on stimulation with oestradiol was inhibited with 50 nM TPA in MCF-7 cells but not in T47D cells. The effects of these treatments on the expression of two well characterised oestrogen responsive genes pNR2(pS2) and pNR100 (Cathepsin-D) were examined. Rather than preventing transcription of these oestrogen responsive genes, TPA alone increased pNR2 and pNR100 levels in MCF-7 cells and the combined effect of oestradiol and TPA had a marked synergistic effect in increasing the transcript levels of these genes. In T47D cells pNR2 transcripts were not detected and the increase in pNR100 mRNA levels were not affected by TPA. We conclude that the inhibitory effects of TPA on the growth stimulation of MCF-7 cells by oestradiol was not due to a general inhibition of the expression of oestrogen responsive genes. An alternative possibility examined was that the growth inhibitory effect of TPA on MCF-7 cells might be due to stimulation of TGF-beta 1, acting as an autocrine inhibitory growth factor. Oestradiol treatment of MCF-7 cells reduced the levels of TGF-beta 1 mRNA whereas TPA produced a marked increase. The combined effect of TPA and oestradiol further increased TGF-beta 1 mRNA above the levels seen with TPA alone. Bryostatin had little effect on TGF-beta 1 expression either alone or in combination with oestradiol. These observations are consistent with the hypothesis that the inhibitory effect of TPA on MCF-7 cells may be partly due to autocrine inhibition by TGF-beta 1.
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PMID:Phorbol ester and bryostatin effects on growth and the expression of oestrogen responsive and TGF-beta 1 genes in breast tumour cells. 191 Dec 15

Expression of the pS2 gene which is transcriptionally controlled by oestrogens in the breast cancer cell line MCF-7 is oestrogen independent in stomach mucosa. We show here that the level of MCF-7 cell pS2 mRNA can also be increased by the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). We further demonstrate, using transient transfection assays, that the -428 to -332 5' flanking sequence of the pS2 gene contains DNA enhancer elements responsive to oestrogens, TPA, EGF, the c-Ha-ras oncoprotein and the c-jun protein.
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PMID:The 5' flanking region of the pS2 gene contains a complex enhancer region responsive to oestrogens, epidermal growth factor, a tumour promoter (TPA), the c-Ha-ras oncoprotein and the c-jun protein. 249 85

In MCF7 human breast cancer cells, cathepsin-D and pS2 mRNAs are specifically and directly induced by estrogens at the transcriptional level. We studied the regulation of expression of these two genes by growth factors that are also mitogenic in this cell line. We show that pS2 mRNA, like cathepsin-D mRNA, is rapidly induced 2- to 4-fold by epidermal growth factor. The effect of epidermal growth factor on these two mRNAs was dependent upon de novo protein synthesis, indicating a different mechanism of regulation than with estradiol. Other peptide growth factors, such as insulin, insulin-like growth factor I, and basic fibroblast growth factor, also increased up to 3-fold the steady state levels of the two mRNAs in MCF7 cells. The pS2 mRNA, but not cathepsin-D mRNA, was also induced up to 8-fold by protein kinase-C activation with 12-O-tetradecanoylphorbol-13-acetate, suggesting the possible involvement of this transduction pathway in pS2 mRNA induction. The effect of 12-O-tetradecanoylphorbol-13-acetate was time and dose dependent and required protein synthesis. In addition, treatment by agents elevating cAMP increased pS2 mRNA accumulation 4-fold, whereas it had no effect on cathepsin-D mRNA levels. These results demonstrate that cathepsin-D and pS2 genes are under complex regulation in MCF7 cells, since growth factors stimulate their expression via indirect mechanisms contrasting with the primary transcriptional effects of estrogens.
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PMID:Regulation of cathepsin-D and pS2 gene expression by growth factors in MCF7 human breast cancer cells. 266 75

In MCF7 human breast cancer cells, the antiestrogens 4-hydroxy-tamoxifen and ICI 164,384 inhibit the mitogenic activity of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). These growth factors also stimulate the expression of cathepsin-D and pS2 genes. Therefore, we studied the effects of antiestrogens on growth factor induction of pS2 and cathepsin-D mRNA. The two antiestrogens strongly inhibited the transcriptional induction of pS2 by growth factors. On the contrary, estradiol and IGF-I or EGF had an additive effect on pS2 mRNA accumulation. Growth factor induction of cathepsin-D was also inhibited by ICI 164,384. By contrast, 4-hydroxytamoxifen had an agonist effect on cathepsin-D and an additive effect on IGF-I-induced mRNA. When 12-O-tetradecanoylphorbol-13-acetate or 8-bromo-cAMP (8-Br-cAMP) was used instead of growth factors, similar effects of 4-hydroxytamoxifen and ICI 164,384 were obtained on pS2 (12-O-tetradecanoylphorbol-13-acetate and 8-Br-cAMP) and cathepsin-D (8-Br-cAMP) induction. A mechanism based on the classical competitive inhibition by antiestrogens of estrogen binding and action on the estrogen receptor was very unlikely, as 1) no antigrowth factor activity was obtained with R5020, which was a potent inhibitor of estrogen induction of pS2 and cathepsin-D mRNA; 2) in the Ishikawa endometrial cancer cell line, the cathepsin-D gene is unresponsive to estrogen, but was inhibited by antiestrogen after its induction by EGF or 8-Br-cAMP; and 3) the residual estrogen concentration in cells was too low to induce the expression of estrogen-specific genes. However, antiestrogens did not inhibit the expression of all genes induced by growth factors, as they were without effect on IGF-I induction of glyceraldehyde-3-phosphate dehydrogenase mRNA. These results demonstrate that antiestrogens can modulate the transcription of some growth factor-induced genes and strongly suggest that this effect is not due to interference with residual estrogens.
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PMID:Synthetic antiestrogens modulate induction of pS2 and cathepsin-D messenger ribonucleic acid by growth factors and adenosine 3',5'-monophosphate in MCF7 cells. 834 99

Exposure of human breast cancer cells (MCF-7) to tumor promoters such as 12-O-tetradecanoyl phorbol 13-acetate (TPA) for 24 h at concentrations of 1-100 nM resulted in marked inhibition of DNA synthesis but a 3-5-fold increase in the amount of pS2 protein in the medium. These results support our previous suggestion that pS2 protein is not involved in the mechanism controlling proliferation of MCF-7 cells. During treatment with TPA, the intracellular content of pS2 protein was constant, suggesting that TPA did not induce secretion of pS2 protein but rather de novo synthesis of the protein. The increase in the pS2 protein content of the medium by TPA was inhibited by simultaneous addition of cycloheximide, but not by that of actinomycin D. Northern-blot hybridization analysis showed that the amount of pS2 mRNA was unchanged by treatment of the cells with TPA. These results indicate that TPA does not induce transcription of the pS2 gene, and suggest that the main effect of TPA results from the induction of translation of pS2 mRNA.
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PMID:Estrogen-inducible pS2 protein is not the key regulatory component in the proliferation of human breast cancer cells (MCF-7). 835 73

Regulation of two genes involved in tumor invasion, the matrix metalloproteinase (MMP)-1 and the tissue inhibitor of MMP (TIMP)-1, by activators of protein kinase C (PKC) or protein kinase A (PKA) was studied in MCF-7 mammary adenocarcinoma cells. The basal mRNA expression was undetectable for MMP-1 and low for TIMP-1. Treatment of MCF-7 cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (100 nM) was associated with a high expression of MMP-1 mRNA, as well as an induction of the level of TIMP-1 mRNA (5- to 10-fold). In the presence of actinomycin D (AMD, 4.0 microM), an inhibitor of transcription, these stimulatory effects of TPA were abolished. Similar responses were observed when protein synthesis was inhibited by cycloheximide (CHX, 50 microM). In the presence of the cyclic AMP (cAMP) analogue N6-benzoyl (N6-Bzl)-cAMP (500 microM), the MMP-1 mRNA was unaffected and still below the level of detection, whereas a non-significant increase (< 2-fold) in TIMP-1 mRNA was observed. The level of pS2 mRNA, of which the induction by TPA in MCF-7 cells is a primary transcriptional event, was up-regulated (10- to 15-fold) by TPA (100 nM), whereas a much weaker increase (2- to 3-fold) was observed by treatment with N6-Bzl-cAMP (500 microM). Again, these stimulatory effects were counteracted by AMD (4.0 microM) and CHX (50 microM). These data suggest that activation of PKC but not of PKA may induce transcription of MMP-1 and TIMP-1, possibly by the synthesis of transcription factor(s), in transformed cells of epithelial origin.
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PMID:Regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in MCF-7 cells: comparison with regulatory mechanisms of pS2 expression. 887 12

Because histone acetylation is implicated in the facilitation of specific gene transcription, the effect of increasing histone acetylation on the expression of an endogenous gene was investigated. The ability of trichostatin A (TSA), a histone deacetylase inhibitor, to potentiate the estradiol (E2) induction of progesterone receptor (PR) levels in MCF-7 cells was studied. Although TSA alone had no effect on PR synthesis, measured by a whole-cell binding assay with [3H]R5020, TSA potentiated the effect of 10(-11) ME2 such that 10 ng of TSA/mL approximately doubled the hormone response. When TSA was removed from the cells after various incubation times (24 and 48 h) by successive washings with TSA-free medium, it was determined that TSA was required throughout the 96-h incubation period in order to achieve maximal potentiation for the E2 response. In addition, TSA potentiated E2 induction of pS2 mRNA. These results suggested that the estrogen receptor (ER) complex might alter histone acetylation as part of the gene activation process. To test this directly, MCF-7 cells were incubated for 48 h with E2 followed by incubation with sodium [3H]acetate for 1 h. From two-dimensional polyacrylamide gel electrophoresis, an increase in total acetate incorporation into histones in estrogen- treated cells compared to control was observed as well as a preferential increase in the mono- and diacetylated histone H4. Experiments with lysine-specific antiacetylated H4 antibodies suggest a preferential increase in acetylation at lysine 16, but not 5, 8, or 12. The results of this study support an important role for histone acetylation in the mechanism of action of the ER.
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PMID:The effects of histone acetylation on estrogen responsiveness in MCF-7 cells. 1070 63

The pS2 promoter is complex with binding sites for a number of protein factors that may participate in modulating its activity. The pS2 gene was transcriptionally activated by estrogens in HepG2 cells transformed (HepER3) to express the estrogen receptor alpha (ERalpha). The phorbol ester phorbol 12-myristate 13-acetate (PMA) stimulated pS2 expression in both HepER3 and the parental, non-ER-expressing HepG2 cells, although its activity was substantially less in HepG2 cells. The use of selective protein kinase inhibitors suggested that the MAPK pathway contributes substantially to estrogen stimulation of the pS2 promoter. The activator protein 1 (AP1) site at -332 to -338 in the pS2 promoter had a dominant role in the response to both estrogens and PMA, although the estrogen response element at -393 to -405 was essential to mediate the response to estrogen. The potentiation of pS2 promoter activity by the AP1 motif in response to estrogen was dependent on the ligand binding domain of ERalpha. Furthermore, the presence of an intact AP1 element in the pS2 promoter sustained suppression of pS2 promoter activity by an LXXLL peptide. In summary, the data suggest that the effect of estrogen is mediated through a cross-talk between the estrogen-responsive element and the AP1 response element and that ERalpha plays a crucial role in mediating the effect of both estrogen and PMA.
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PMID:pS2 Gene expression in HepG2 cells: complex regulation through crosstalk between the estrogen receptor alpha, an estrogen-responsive element, and the activator protein 1 response element. 1202 87

Although the expression of the metastases-associated gene MTA1 correlates with tumor metastases, its role in regulating type IV collagenase expression is unknown. Enforced MTA1 expression in HT1080 cells reduced basal and 12-myristate 13-acetate-induced 92-kDa type IV collagenase (MMP-9) protein/mRNA levels. DNase I hypersensitivity and PstI accessibility assays revealed multiple regions of the MMP-9 promoter (-650/-450 and -120/+1), showing reduced hypersensitivity in the MTA1-expressing cells. Chromatin immunoprecipitation assays demonstrated MTA1 binding to the distal region, which spans several regulatory cis elements. Co-immunoprecipitation and chromatin immunoprecipitation assay experiments revealed histone deacetylase 2 (HDAC2)-MTA1 protein-protein interactions and the MTA1-dependent recruitment of HDAC2 to the distal MMP-9 promoter region, yielding diminished histone H3/H4 acetylation. However, HDAC2 binding and H3/H4 acetylation at the proximal MMP-9 region were unaffected by MTA1 expression. Furthermore, trichostatin treatment only partially relieved MTA1-repressed MMP-9 expression, indicating a HDAC-insensitive component possibly involv ing the nucleosome-remodeling Mi2 activity, which was recruited to the promoter by MTA1. In summary, (a) MMP-9 adds to a short list of MTA1-regulated genes, which so far only includes c-myc and pS2, and (b) MTA1 binds to the MMP-9 promoter, thereby repressing expression of this type IV collagenase via histone-dependent and independent mechanisms.
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PMID:Repression of 92-kDa type IV collagenase expression by MTA1 is mediated through direct interactions with the promoter via a mechanism, which is both dependent on and independent of histone deacetylation. 1243 81

Gp-340 is a glycoprotein belonging to the scavenger receptor cysteine rich (SRCR) group B family. It binds to host immune components such as lung surfactant protein D (SP-D). Recent studies found that gp-340 interacts directly with pathogenic microorganisms and induces their aggregation, suggesting its involvement in innate immunity. In order to investigate further its potential immune functions in the appropriate cell lines, the expression of gp-340 in four conventional immune cell lines (U937, HL60, Jurkat, Raji), and two innate immune-related epithelial cell lines (A549 derived from lung and AGS from stomach), was examined by RT-PCR and immunohistochemistry. The resting immune cell lines showed weak or no gp-340 mRNA expression; while the two epithelial cell lines expressed gp-340 at much higher level, which was differentially regulated by phorbol myristate acetate (PMA) treatment. In the A549 cells, gp-340 was up-regulated along with the PMA-induced proinflammatory expression of both IL-6 and IL-8. In AGS cells, PMA down-regulation of gp-340 was seen in parallel with an up-regulation of the two mature gastric epithelial specific proteins TFF1 (trefoil factor 1) and TFF2, which are implicated as markers of terminal differentiation. Analysis of the distribution of gp-340, together with the TFFs and SP-D in normal lung and gastric mucosa, supported further our in vitro data. We conclude that the differential regulation of gp-340 in the two epithelial cell lines by PMA indicates that gp-340 s involvement in mucosal defence and growth of epithelial cells may vary at different body locations and during different stages of epithelial differentiation.
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PMID:The scavenger receptor, cysteine-rich domain-containing molecule gp-340 is differentially regulated in epithelial cell lines by phorbol ester. 1245 35


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