Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous reports have shown that progestins stimulate the proliferation of the human breast cancer cell line T47D in culture. Under different conditions other reports have shown progestin stimulation, inhibition or no effect on growth. It has also been shown that c-myc expression is stimulated at early times by progestins. We are currently testing the hypothesis that the mechanism of growth enhancement by progestins involves the stimulation of expression of c-myc. This hypothesis predicts a progesterone regulatory region in or near the c-myc gene. We have identified a region, from -2327 to -1833, which serves this function. This region includes a 15 bp sequence with homology to the PRE (progesterone response element) consensus sequence. Human progesterone receptor (PR) binds to this sequence in a specific, ligand-enhanced manner in electrophoretic mobility shift assays (EMSA). A 3507 bp HindIII-XbaI fragment of the 5' flanking region of the c-myc gene, -2327 to +1180, containing the progestin regulatory region and the c-myc promoter, confers progestin responsiveness to the CAT (chloramphenicol acetyl transferase) reporter gene in progesterone receptor (PR)-rich T47D human breast cancer cells, but not in PR-negative MDA-MB-231 cells. Removal of the progestin regulatory region abrogates progestin responsiveness. These data demonstrate that the sequence from -2327 to -1833 of the human c-myc gene includes a positive progestin regulatory region.
J Steroid Biochem Mol Biol 1997 Jul
PMID:A sequence in the 5' flanking region confers progestin responsiveness on the human c-myc gene. 940 78

Despite an intriguing cell biology and the suggestion of a role in pathophysiological responses, the mechanism of action of such lipid phosphoric acid mediators as lysophosphatidic acid (LPA) remains obscure, in part because of an underdeveloped medicinal chemistry. We report now the agonist activity of a synthetic phospholipid in which the glycerol backbone of LPA is replaced by L-serine. Like LPA, the L-serine-based lipid mobilizes calcium and inhibits activation of adenylyl cyclase in the human breast cancer cell line MDA MB231. Treatment with LPA desensitizes MDA MB231 cells to subsequent application of the L-serine compound; when the order of application is reversed, however, the L-serine compound does not prevent calcium mobilization by LPA, which might indicate the existence of two LPA receptors in these cells. The analogous D-serine-based phospholipid was distinctly less potent than the L-isomer in those assays; this finding demonstrates stereoselectivity by an LPA receptor. Unlike LPA, the L-serine-based lipid does not evoke a chloride conductance in Xenopus laevis oocytes, but injection of poly(A)+ RNA from HEK 293 cells confers this phenotype on the oocyte. The latter result has practical importance in that it allows use of the frog oocyte for expression cloning of an LPA receptor DNA, an assay system made problematic by the oocyte's strong endogenous response to LPA.
Mol Pharmacol 1998 Feb
PMID:Characterization of a receptor subtype-selective lysophosphatidic acid mimetic. 946 75

Using microcell-mediated transfer of a normal chromosome 11 into the highly metastatic MDA-MB-435 human breast carcinoma cell line, we previously showed that human chromosome 11 contains a metastasis-suppressor gene for breast cancer. A known metastasis-suppressor gene, kai-1, and a related family member, tapa-1, have been mapped to chromosome 11p11.2 and 11p15.5, respectively. To determine if these genes are responsible for the metastasis suppression seen in our microcell hybrids, we examined their expression by western blot analysis. Although tapa-1 expression did not significantly correlate with metastasis suppression, kai-1 production was dramatically increased in the metastasis-suppressed chromosome 11 microcell hybrids and unchanged in the metastatic chromosome 6 controls. Transfection of full-length kai-1 cDNA into MDA-MB-435 cells resulted in clones that did not have a significantly decreased in vivo incidence of lung metastases. However, western blot analysis showed that the primary tumors and the metastatic lesions of the transfectants had decreased levels of kai-1 protein compared with the inoculated cells. Furthermore, several of the transfectant clones expressed heavily modified kai-1 protein compared with that of the microcell hybrids. Our data indicate that protein modification may affect the normal function of kai-1 in vivo and that a threshold level of kai-1 protein expression may be necessary for suppression of the metastatic phenotype.
Mol Carcinog 1998 Feb
PMID:Correlation between reduction of metastasis in the MDA-MB-435 model system and increased expression of the Kai-1 protein. 949 11

MDA-MB-468 is a human mammary adenocarcinoma cell line that overexpresses the epidermal growth factor (EGF) receptor and undergoes programmed cell death (apoptosis) in response to EGF treatment. Programmed cell death was shown to be greatly enhanced when cells were growth-arrested prior to EGF treatment. Apoptosis was characterized by an initial rounding up and detachment of the cells from their substrate starting about 12 h after EGF treatment, followed by chromatin condensation, nuclear fragmentation and oligonucleosomal fragmentation of the DNA at about 24 to 48 h. Cell death was dependent on de novo protein synthesis. We found a rapid induction of c-fos, c-jun and junB at the mRNA level after about 30 min of EGF treatment and a more delayed upregulation of fosB and fra-1. The junD gene was expressed in the absence of EGF, and it was moderately induced within 30 min of growth factor addition. The increase of the different fos and jun mRNAs were paralleled by an increase of activator protein-1 (AP-1) DNA binding activity. A characterization of the AP-1 complex revealed similar levels of several Fos and Jun proteins. Based on the kinetics of AP-1 accumulation and cell death, it seems likely that AP-1 contributes to the apoptotic cell death of EGF receptor-overexpressing MDA-MB-486 cells.
Cell Mol Life Sci 1998 Feb
PMID:EGF-induced programmed cell death of human mammary carcinoma MDA-MB-468 cells is preceded by activation AP-1. 953 53

We recently reported that a p53 encoding plasmid (BAP-p53) complexed to liposomes administered intravenously markedly attenuates the growth of a malignant human breast tumor. We now have found that systemically delivered liposomes complexed to a plasmid expressing an established antiangiogenic peptide of thrombospondin I (BAP-TSPf) decreased the growth of MDA-MB-435 tumors compared to controls in nude mice. Compared to BAP-p53, the BAP-TSPf group had a similar antitumor efficacy. More importantly, liposomes complexed with BAP-TSPf and BAP-p53 synergistically decreased the growth of MDA-MB-435 tumors when compared to either BAP-p53 or BAP-TSPf alone. Furthermore, we also determined that the combination therapy of p53 and TSPf inhibited endothelial cells in vitro more than either p53 or TSPf alone. There was also a significant decrease of the blood vessel density in the combination p53 and TSPf treatment group compared to the control groups. These results suggest that liposomes complexed to a tumor suppressor and antiangiogenic genes may be effective in treating metastatic tumors.
Mol Genet Metab 1998 Feb
PMID:Gene therapy with p53 and a fragment of thrombospondin I inhibits human breast cancer in vivo. 956 63

We have shown that 4-hydroxytamoxifen (4-OHT) has estrogen-like effects on induction of TGFalpha mRNA in estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells, transfected with either wildtype (S30 cells) or a codon 351asp-->tyr mutant ER (BC-2 cells). The mutant receptor used to produce the stable transfectants was identified in a tamoxifen-stimulated human breast tumor. We have also demonstrated that raloxifene exhibits a gene-specific estrogen-like effect with mutant ER (BC-2 cells) but not with wildtype ER (S30 cells) (Levenson, A.S., Catherino, W.H. and Jordan, V.C. (1997) Estrogenic activity is increased for an antiestrogen by a natural mutation of the estrogen receptor. J. Steroid Biochem. Mol. Biol., 60, 261-268). We now describe the regulation of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) endogenous gene expression by estradiol (E2) and different antiestrogens in BC-2 cells. Northern blot analyses revealed that 4-OHT and raloxifene have concentration-dependent agonistic (E2-like) effects on the regulation of these genes. In contrast, the pure antiestrogen ICI 182780 alone had no effect but could block the action of E2, 4-OHT and raloxifene. The E2-like effects of non-steroidal antiestrogens in this model system cannot be explained by the mutation in the ER alone because 4-OHT acts as an agonist with wildtype receptor as well. We propose that the clear cut biological expression of estrogen-like qualities with different antiestrogens will in the future serve as an important model to dissect the signal transduction pathway.
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PMID:Agonist activity of antiestrogen-receptor complexes to regulate urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) endogenous gene expression in breast cancer cells. 956 18

The Bcl2 family of proteins plays a significant role in regulation of apoptosis. In this study, the microtubule-damaging drugs paclitaxel, vincristine, and vinblastine induced Bcl2 hyperphosphorylation and apoptosis in MCF-7 and MDA-MB-231 cells and reduced Bcl2-Bax dimerization. Paclitaxel or vincristine induced increased expression of Bax, while overexpression of Bcl2 in these cell lines counteracted the effects of low doses of these drugs. In addition, paclitaxel- and vincristine-induced activation of cyclic AMP (cAMP)-dependent protein kinase (protein kinase A [PKA]) induced Bcl2 hyperphosphorylation and apoptosis, which were blocked by the PKA inhibitor Rp diastereomers of cAMP (Rp-cAMP). This finding suggests that activation of PKA due to microtubule damage is an important event in Bcl2 hyperphosphorylation and induction of apoptosis. These microtubule-damaging drugs caused growth arrest in G2-M phase of the cell cycle and had no effect on p53 induction, suggesting that hyperphosphorylation mediated inactivation of Bcl2 and apoptosis without the involvement of p53. By comparison, the DNA-damaging drugs methotrexate and doxorubicin had no effect on Bcl2 hyperphosphorylation but induced p53 expression. Interestingly, paclitaxel or vincristine induced activation of caspase 3 and cleavage of poly(ADP-ribose) polymerase downstream of Bcl2 hyperphosphorylation. These data suggest that there may be a signaling cascade induced by agents that disrupt or damage the cytoskeleton that is distinct from (i.e., p53 independent), but perhaps related to (i.e., involves kinase activation and leads to apoptosis), the cellular response to DNA damage.
Mol Cell Biol 1998 Jun
PMID:Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. 958 91

Tissue factor (TF) is a cell-surface glycoprotein responsible for initiating the extrinsic pathway of coagulation. The overexpression of TF in human malignancy has been correlated with the angiogenic phenotype, poor prognosis, and thromboembolic complications. The mechanisms underlying constitutive expression of TF in cancer cells are poorly defined. We cloned TF cDNA on the basis of its strong expression in metastatic MDA-MB-231 breast carcinoma cells in contrast to its weak expression in non-metastatic MCF-7 cells. Transient transfection analysis showed that TF promoter activity in MCF-7 cells could be stimulated by expression of a membrane-targeted raf kinase (raf-CAAX). raf-induced activity was dependent on the presence of an AP-1/NF-kappaB motif in the TF promoter and was inhibited by dominant-negative mutants of jun and by I-kappaB alpha. MDA-MB-231 cells were found to contain higher levels of ERK1/2 kinase activity than did MCF-7 cells. Electrophoretic mobility shift assays showed that MDA-MB-231 nuclear proteins bound strongly to an oligonucleotide corresponding to the AP-1/NF-kappaB sequence, whereas MCF-7 nuclear extracts showed weak binding to this element. Finally, we showed that TF mRNA levels in MDA-MB-231 cells declined after addition of the mitogen-activated protein kinase kinase inhibitor PD98059. Our data showed that activation of the raf-ERK pathway led to activation of TF expression in breast carcinoma cells and suggested that constitutive activation of this pathway leads to high TF expression in MDA-MB-231 cells.
Mol Carcinog 1998 Apr
PMID:Activation of tissue-factor gene expression in breast carcinoma cells by stimulation of the RAF-ERK signaling pathway. 958 53

In C3H/10T1/2 murine fibroblasts, overexpression of both c-Src and the human epidermal growth factor (EGF) receptor 1 (HER1) is required for detection of stable complexes between the two molecules and results in hyperactivation of the receptor and synergistic increases in tumor formation in nude mice, as compared with cells that overexpress only one of the pair. Elevated levels or activities of c-Src and HER1 also occur in a subset of later-stage breast cancers, suggesting that interactions between these two molecules could contribute to a more aggressive clinical course. To determine whether stable complexes between c-Src and HER1 occur in human breast cancers under the same conditions as in murine fibroblasts and whether the appearance of such complexes correlates with enhanced signaling through the EGF receptor and increased tumor growth, human breast tumor cell lines and tumor tissues were analyzed for a number of c-Src/HER1-mediated signaling events and tumorigenicity. In a panel of 14 cell lines, 10 overexpressed c-Src, and of these, five contained elevated levels of HER1 and exhibited an EGF-dependent association between HER1 and c-Src. This association was also present in a HER1/c-Src-overexpressing tumor sample from a breast cancer patient. Further analysis of signaling events revealed that phosphorylation of the HER1 substrate, Shc, and its downstream effector, mitogen-activated protein kinase, was increased in EGF-stimulated MDA-MB-468, MDA-MB-231, and BT-549 cells (which overexpress both c-Src and HER1) as compared with MCF7 and ZR-75-1 cells (which only overexpress c-Src). Furthermore, MDA-MB-468 and MDA-MB-231 cells displayed increased tumorigenicity in nude mice. These results support the hypothesis that c-Src/HER1 interactions contribute to tumor progression in certain late-stage breast tumor cells.
Mol Carcinog 1998 Apr
PMID:Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. 958 56

Retinoic acid receptor alpha 1 (RAR alpha 1) gene expression is induced by 17 beta-estradiol (E2) in estrogen receptor (ER)-positive breast cancer cells, and the -100 to -49 region of the RAR alpha 1 gene promoter was previously shown to be required for E2-responsiveness. This region of the RAR alpha 1 promoter was further analyzed using the following oligonucleotides: -100 to -49 (RAR4); -79 to -56 (RAR3); -79 to -49 (RAR2); -100 to -58 (RAR1); and their derived promoter reporter constructs (pRAR4, pRAR3, pRAR2, and pRAR1). In transient transfection studies in MCF-7 human breast cancer cells, pRAR2 and pRAR1 were E2-responsive; both of the RAR alpha 1 gene promoter inserts contained two GC-rich sites and bound Sp1 protein in gel mobility shift assays. Using wild-type [32P]RAR2 and oligonucleotides mutated in one or both GC-rich sites, it was shown that ER enhanced Sp1 binding to both sites, but a ternary ER-Sp1-DNA complex was not observed in gel mobility shift assays. In transient transfection assays, each of the GC-rich motifs were sufficient for E2-induced transactivation. In ER-negative MDA-MB-231 cells transiently transfected with pRAR2, E2 responsiveness was observed only in cells cotransfected with wild-type ER or 11C-ER containing a deletion of the DNA-binding domain but not with ER variants that express activation function-1 (AF-1) or AF-2. Using a similar approach, it was shown that the GC-rich sites in RAR1 were also sufficient for ER activation. These results demonstrate that interaction of a transcriptionally active ER/Sp1 complex with GC-rich motifs is required for hormone inducibility of the downstream region of the RAR alpha 1 gene promoter.
Mol Endocrinol 1998 Jun
PMID:Estrogen-induced retinoic acid receptor alpha 1 gene expression: role of estrogen receptor-Sp1 complex. 962 63


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