Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human progesterone receptor (PR) is a member of the steroid/thyroid hormone superfamily of nuclear receptors. The receptor is expressed as two forms, PR-B and the shorter PR-A, which lacks the NH2-terminal 164 amino acids of PR-B; whereas PR-B seems to be predominantly a transcriptional activator, PR-A also functions as a repressor. Our previous studies of PR expressed in T47D breast cancer cells have shown that PR is a phosphoprotein whose phosphorylation is enhanced in response to hormone. There is an initial rapid (minutes) increase in phosphorylation followed by a slower, less substantial increase, which results in decreased mobility of the receptor on sodium dodecyl sulfate gels. We now report the identification of three phosphorylation sites, which are predominantly phosphorylated during the later phase of the response to hormone. These sites, Ser102, Ser294, and Ser345, are all found in Ser-Pro consensus sequences. Whereas Ser294 and Ser345 are common to PR-A and PR-B, Ser102 is unique to PR-B. Finally, we demonstrate that phosphorylation of Ser345 is associated with the altered mobility on sodium dodecyl sulfate gels.
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PMID:Identification of a group of Ser-Pro motif hormone-inducible phosphorylation sites in the human progesterone receptor. 747 77

Alterations in the tumor suppressor gene p53 are the most commonly identified changes in cancer, including neoplasia of the breast. The activity of p53 is regulated post-translationally. Phosphorylation state, subcellular localization, and interaction with any of a number of cellular proteins are likely to influence the function of p53. The exact effect of p53-mediated growth suppression seems to be cell-type specific but appears to be directly related to the ability of p53 to act as a specific transcriptional activator. The role that transcriptional repression plays in the function of WT p53 is less clear. It is also possible that p53 has a more direct activity in DNA replication and repair. Most documented p53 mutations result in single amino acid substitutions which may confer one or more of a spectrum of transforming abilities on the protein. Mutation may lead to nuclear accumulation of p53 protein; however, inactivation of p53 by nuclear exclusion and interaction with the mdm2 protein also appear to be important in tumorigenesis. Used in conjunction with other established factors, accumulation of cellular p53 may be a useful prognostic indicator in breast cancer. A syngeneic mouse model system yielded evidence that p53 mutations are important in the early, preneoplastic stages of mammary tumorigenesis. This murine system may provide the ability to investigate the functions of p53 in the early stages of breast cancer which are technically difficult to examine in the human system.
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PMID:Tumor suppressor p53 mutations and breast cancer: a critical analysis. 779 21

The mechanism of negative growth regulation by the nuclear phosphoprotein p53 in breast cancer cells may rely on its role as a transcriptional activator of cell cycle-related genes. We have tested this hypothesis using retrovirally transduced wild-type (wt) p53 in breast cancer cell lines containing homozygously endogenous mutant (mt) p53. Restoring the expression of wt p53, the percentage of cells in S phase was reduced, G1/S transition was slowed, and progression through S was restrained. The fraction of cells with a flattened "Cdk-minus" phenotype increased 5- to 10-fold. High constitutive mRNA expression of the cyclin-Cdk inhibitor WAF1 in MDAMB231 cells was not induced upon restored wt p53 expression suggesting a p53-independent pathway in the regulation of WAF1 mRNA expression. Wt p53 acted trans-dominantly in the presence of accumulating mt p53 and installed a modulation of G1/S transition and S phase progression independent of WAF1 expression.
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PMID:Retrovirally mediated wild-type p53 restores S-phase modulation without inducing WAF1 mRNA in breast carcinoma cells containing mutant p53. 874 22

In humans, the biological response to progesterone is mediated by two distinct forms of the progesterone receptor (human (h) PR-A, 94 kDa and hPR-B, 114 kDa). These two isoforms are transcribed from distinct estrogen-inducible promoters within a single copy PR gene; the only difference between them is that the first 164 amino acids of hPR-B (B-upstream sequence) are absent in hPR-A. In most cell lines such as MCF-7 (human breast cancer cells), CV-1 (monkey kidney fibroblasts), and HeLa (human cervical carcinoma cells), hPR-A functions as a transcriptional repressor, whereas hPR-B functions as a transcriptional activator of progesterone-responsive genes. Interestingly, in these cell contexts, hPR-A also acts as a trans-dominant repressor of the transcriptional activity of other steroid hormone receptors. In contrast to hPR-A, which functions predominantly as a ligand-dependent transcriptional repressor, we show in this study that the A isoform of the chicken PR (cPR-A) lacks this trans-dominant repressor function and is a transcriptional activator in all contexts examined. By constructing chimeras between the N-terminal domains of the chicken and human PR, we mapped the trans-dominant repressor function of hPR-A to the first 140 amino acids of the protein. Notably, when this 140-amino acid "repressor" domain is placed onto chicken PR-A, the activity of the latter changes from a transcriptional activator to a repressor. Interestingly, however, this "repressor domain" is necessary, but not sufficient, for trans-repression as it is inactive when it is tethered to a heterologous protein. This suggests that the trans-repression function is comprised not only of the repressor domain of hPR-A but also requires the context of the receptor to function. The identification of a discrete inhibitory region within hPR-A which is transferable to another receptor implies that this region interacts with a set of transcription factors or adaptors that are distinct from those recognized by hPR-B, the identification of which will be required to define the mechanism by which hPR-A modulates steroid hormone receptor transcriptional activity. Thus, although chickens and humans both produce two very similar forms of the progesterone receptor, it is clear from these studies that the mechanism of action of progesterone in these two systems is quite different.
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PMID:Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. 940 67

The breast and ovarian cancer susceptibility gene BRCA1, is a nuclear phosphoprotein which functions as a tumor suppressor in human breast cancer cells. BRCA1 protein contains an amino-terminal zinc finger motif and a carboxy-terminal acidic region. Recently, the carboxy-terminal region of BRCA1 and the amino-terminal region of BRCA2 proteins were shown to function as transactivation domains when fused to GAL4 DNA binding domain. We have recently isolated and characterized two new naturally occurring variants of BRCA1 (BRCA1a/p110 and BRCA1b/p100) which are phosphoproteins containing phosphotyrosine that associate with E2F transcriptional factors, cyclins and cyclin dependent kinases indicating a role for BRCA1 proteins in cell-cycle regulation. Here we show for the first time that the amino-terminal region of BRCA1a (BNT) but not BRCA1b can also function as a transcriptional activator when fused to GAL4 DNA binding domain. Thus, BRCA1/1a proteins contain two autonomous transcriptional activation domains, one at the amino-terminal region (BNT) and the other at the carboxy-terminal region (BCT). BRCA1b retains only the BCT domain since it has lost part of the potential BNT domain as a result of alternative splicing. Our results also suggest the presence of an inhibitory domain at the carboxy terminal region of BRCA1 and BRCA1a proteins (BID). Thus, BRCA1b protein may function as a dominant negative variant that could regulate the transcriptional activity of BRCA1/BRCA1a proteins and hence may serve as a marker for identifying individuals with greater potential for developing breast cancer. It may be possible that loss of transcriptional activation or protein-protein interactions in patients with mutations in the amino terminal zinc finger domain could deprive the cell of an important mechanism for regulating cell proliferation leading to the development of breast cancer.
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PMID:Differential transcriptional activation by the N-terminal region of BRCA1 splice variants BRCA1a and BRCA1b. 953 56

The epithelium-specific transcription factor, ERT/ESX/ESE-1/ELF3, binds to the TGF-beta RII promoter in a sequence specific manner and regulates its expression. In this study, we investigated whether ERT could regulate endogenous TGF-beta RII expression in Hs578t breast cancer cells. Analyses of the Hs578t parental cell line revealed low RII mRNA expression and resistance to the growth inhibitory effects of TGF-beta. Infection of this cell line with a retroviral construct expressing ERT induced higher levels of endogenous RII mRNA expression and protein expression relative to cells infected with chloramphenicol acetyltransferase (CATneo) as a control. Relative to control cells, the ERTneo-expressing Hs578t cells show approximately a 50% reduction in cell growth in the presence of exogenous TGF-beta1, as well as a fourfold higher induction of activation in transient transfection assays using the 3TP-luciferase reporter construct. When transplanted into athymic mice, ERT-expressing Hs578t cells showed decreased and delayed tumorigenicity compared with control cells. This data strongly suggests that ERT plays an important role as a transcriptional activator of TGF-beta RII expression, and that deregulated ERT expression may play a critical role in rendering Hs578t human breast cancer cells insensitive to TGF-beta's growth inhibitory effects.
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PMID:Over-expression of ERT(ESX/ESE-1/ELF3), an ets-related transcription factor, induces endogenous TGF-beta type II receptor expression and restores the TGF-beta signaling pathway in Hs578t human breast cancer cells. 1064 90

Heregulin beta1 (HRG), a combinatorial ligand for human epidermal growth factor receptor 3 and human epidermal growth factor receptor 4 receptors, is a regulatory secretory polypeptide with distinct biological effects such as growth stimulation, differentiation, invasiveness, and migration in breast cancer cells. The mechanism underlying the diverse functions of HRG is not well established, but it is believed to be dependent on the induced changes in expression of specific cellular gene products, their modification, or both. The binding of basic leucine zipper transcription factors to the cAMP response element is known to activate a variety of gene products with a role or roles in growth regulation. In the studies presented here, we identified basic leucine zipper activating transcription factor (ATF) 4 as one of the HRG-inducible gene product. We demonstrated that HRG stimulation of human cancer cells induces expression of ATF4 mRNA and protein, ATF4 DNA binding activity, and ATF4 transactivating function. Consistent with its role as a transcriptional activator, HRG-stimulated ATF4 protein stimulated the transcription from an artificial promoter with three tandem ATF sites or from a naturally occurring promoter with ATF4 sites such as E-selectin. We also demonstrated a preferential role of the HRG-stimulated mitogen-activated protein kinase pathway, but not the phosphatidylinositol 3'-kinase pathway, in supporting the observed increase in ATF4 DNA binding activity and transcription from E-selectin promoter in HRG-stimulated cells. Because ATF4 binding sites are present in a variety of growth-regulating cellular genes, these findings suggest that the stimulation of ATF4 expression and its transactivating functions may constitute an important mechanism of HRG-mediated regulation of putative genes with diversified functions. The present study is the first demonstration of regulation of expression and transactivation ability of ATF4 by any polypeptide growth factor.
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PMID:Heregulin induces expression, DNA binding activity, and transactivating functions of basic leucine zipper activating transcription factor 4. 1066 76

Genistein, a natural flavone found in soy has been postulated to be responsible for lowering the rate of breast cancer in Asian women. Our previous studies have shown that genistein exerts multiple suppressive effects on both estrogen receptor positive (ER+) as well as estrogen receptor negative (ER-) human breast carcinoma lines suggesting that the mechanisms of these effects may be independent of ER pathways. In the present study however we provide evidence that in the ER+ MCF-7, T47D and 549 lines but not in the ER-MDA-MB-231 and MDA-MB-468 lines both presumed "ER-dependent" and "ER-independent" actions of genistein are mediated through ER pathways. Genistein's antiproliferative effects are estrogen dependent in these ER+ lines, being more pronounced in estrogen-containing media and in the presence of exogenous 17-beta estradiol. Genistein also inhibits the expression of ER-downstream genes including pS2 and TGF-beta in these ER+ lines and this inhibition is also dependent on the presence of estrogen. Genistein inhibits estrogen-induced protein tyrosine kinase (PTK) activity. Genistein is only a weak transcriptional activator and actually decreases ERE-CAT levels induced by 17-beta estradiol in the ER+ lines. Genistein also decreases steady state ER mRNA only in the presence of estrogen in the ER+ lines thereby manifesting another suppression of and through the ER pathway. Our observations resurrect the hypothesis that genistein functions as a "good estrogen" in ER+ breast carcinomas. Since chemopreventive effects of genistein would be targeted to normal ER-positive ductal-lobular cells of the breast, this "good estrogen" action of genistein is most relevant to our understanding of chemoprevention.
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PMID:Genistein's "ER-dependent and independent" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines. 1095 3

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1alpha and HIF-1beta subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1alpha expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1alpha for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1alpha. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1alpha expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1alpha but instead stimulates HIF-1alpha synthesis in a rapamycin-dependent manner. The 5'-untranslated region of HIF-1alpha mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1alpha expression.
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PMID:HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. 1135 7

To gain better understanding of the molecular alterations responsible for the aggressive growth potential of epidermal growth factor receptor (EGFR)-positive breast cancers, we utilized an expression cloning strategy to seek gene products that mediate the EGF-independent growth of human breast cancer cells. A retroviral cDNA expression library was constructed from the EGFR-positive SUM-149PT cell line, and transduced into growth factor-dependent human mammary epithelial (HME) cells. Recipient cells were functionally selected for their ability to proliferate in serum-free, EGF-free medium. Library cDNAs were recovered from EGF-independent colonies by PCR amplification or by biological rescue. Clone H55a#1 contained a library insert encoding amphiregulin. This EGFR ligand was able to confer EGF independence when transduced into HME cells. SUM-149PT and H55a#1 cells overexpressed amphiregulin transcripts, and secreted moderate EGF-like activity in conditioned media, indicating a possible autocrine loop. EGFR membrane levels and constitutive phosphorylation were consistent with this hypothesis, as well as the sensitivity of the cells to an ErbB-specific kinase inhibitor. Expression of the WT1 Wilms' tumor suppressor gene, a transcriptional activator of amphiregulin, did not parallel amphiregulin transcript levels, suggesting that another factor regulates amphiregulin in SUM-149PT. Our data confirm the importance of amphiregulin in the etiology of breast cancer.
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PMID:A functional screen for genes inducing epidermal growth factor autonomy of human mammary epithelial cells confirms the role of amphiregulin. 1149 30


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