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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have analyzed interaction of coactivators with the wild-type estrogen receptor alpha (ER), HEG0, and a mutant, L536P-HEG0, which is constitutively active in several transiently transfected cells and a HeLa line that stably propagates an estrogen-sensitive reporter gene. Different classes of coactivators do not recognize the ER ligand binding domain (LBD) in the same manner. Steroid receptor coactivator-1 (SRC-1), amplified in breast cancer-1 (AIB-1), transcriptional intermediary factor-1 (TIF-1), transcriptional intermediary factor-2 (TIF-2), and receptor interacting protein 140 (RIP140) interacted with HEG0 and L536P-HEG0 in the presence of estradiol, but generally not in the presence of anti-estrogens. However, ICI164,384 stimulated some interaction of RIP140 with LBDs. SRC-1, AIB-1, and RIP140 interacted constitutively with the L536P ER, whereas TIF-1 and TIF-2 interacted only weakly in the absence of hormone. Reciprocal competition for binding to the ER LBD was observed between different classes of coactivators. Moreover, coexpression of RIP140 blocked enhanced transactivation by HEG0 observed in the presence of TIF-2, suggesting that RIP140 may play a negative role in ER signaling. We conclude that constitutive activity of L536P-HEG0 is manifested to similar degrees in different cell types and likely arises from constitutive coactivator binding; different classes of coactivators recognize distinct but overlapping binding sites on the ER LBD. Finally, the observation that L536P-HEG0 interacted constitutively with AIB-1, a coactivator that has been implicated in ER signaling in breast and ovarian cancer, suggests that similar mutations in the ER may contribute to hormone-independent proliferation of breast and ovarian cells.
...
PMID:Different classes of coactivators recognize distinct but overlapping binding sites on the estrogen receptor ligand binding domain. 977 63

To investigate the estrogenic effects on the transcriptional regulation of the epidermal growth factor (EGF) receptor (EGFR) gene, we assayed its promoter ability to direct transcription of the luciferase reporter gene after transfection into HeLa cells. Our studies demonstrated a dose-dependent activation of the EGFR gene transcription by ligand-bound estrogen receptor alpha (ERalpha). This action was retained by the 36-bp core promoter fragment and did not require the receptor DNA binding domain, as demonstrated by analyzing the role of ERalpha deletion mutants on EGFR gene promoter-derived constructs. The 36-bp promoter fragment does not contain an estrogen response element but an imperfect thyroid hormone response element half-site that overlaps the Sp1 binding site. ERalpha does not bind this imperfect thyroid hormone response element half-site but is able to enhance binding of Sp1 to its site, in gel mobility shift assays, suggesting that the mechanism by which the receptor stimulated the transcription involved protein-protein interactions that replaced DNA binding. To explain this action, we propose a model in which induction of the EGFR gene expression by estrogens in HeLa cells is dependent upon the formation of a transcriptionally active ERalpha-Sp1 complex that binds to the GC-rich (Sp1) region of the minimal promoter.
...
PMID:Identification of an estrogen-mediated deoxyribonucleic acid-binding independent transactivation pathway on the epidermal growth factor receptor gene promoter. 1083 Mar 17

17beta-Estradiol (E2) induces c-fos protooncogene expression in MCF-7 human breast cancer cells, and deletion analysis of the c-fos promoter showed that the serum response element (SRE) at -325 to -296 was E2-responsive. The mechanism of ligand-activated estrogen receptor alpha (ERalpha)-dependent activation of gene expression through the SRE was determined by mutational analysis of the promoter, analysis of mitogen-activated protein kinase (MAPK) pathway activation by E2, and transforming growth factor alpha (TGF-alpha) as a positive control. In addition, ERalpha-negative MDA-MB-231 breast cancer and Chinese hamster ovary cells were used as reference cell lines. The results showed that transcriptional activation of the SRE by E2 was due to ERalpha activation of the MAPK pathway and increased binding of the serum response factor and Elk-1 to the SRE. Subsequent studies with dominant negative Elk-1, wild type, and variant GAL4-Elk-1 fusion proteins confirmed that phosphorylation of Elk-1 at serines 383 and 389 in the C-terminal region of Elk-1 is an important downstream target associated with activation of an SRE by E2. Both E2 (ERalpha-dependent) and growth factors (ERalpha-independent) activated the SRE in breast cancer cells via the Ras/MAPK pathway; however, in ER-negative CHO cells that do not express a receptor for TGF-alpha, only hormone-induced activation was observed in cells transfected with ERalpha.
...
PMID:Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1. 1114 55

We recently identified CGA (coding for the alpha subunit of glycoprotein hormones) as a new estrogen receptor alpha (ER alpha)-responsive gene in human breast tumors. Here, we assessed the relationship between CGA status (as determined by real-time quantitative RT-PCR) and the response to tamoxifen therapy in a well-defined cohort of 125 ER alpha-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone. CGA overexpression, observed in 37.6% of patients, was associated with good relapse-free survival (P=0.037; univariate analysis). CGA status, combined with ERBB2 status (a marker of poor outcome), was an independent predictor of the response to tamoxifen (P=0.020; multivariate analysis). CGA status, especially when combined with ERBB2 status, may thus provide useful predictive information on tamoxifen responsiveness in breast cancer.
...
PMID:The CGA gene as new predictor of the response to endocrine therapy in ER alpha-positive postmenopausal breast cancer patients. 1168 75

The estrogen receptor alpha (ERalpha) signaling plays an essential role in breast cancer progression and endocrine therapy. Mitogen-activated protein kinase (MAPK/Erk1/2) has been implicated in ligand-independent activation of ER, resulting in the cross-talk between growth factor and ER mediated signaling. In this study, we examined the effect of the cross-talk on estradiol (E(2))-mediated signaling, tumor growth and its effect on anti-estrogen therapy. Our findings demonstrate that expression of constitutively activated mitogen activated kinase kinase (MEK1), an immediate upstream activator of MAPK in estrogen receptor positive MCF-7 breast cancer cells (MEK/MCF-7), showed an increase in ERalpha-driven transcriptional activation. In MEK/MCF-7 cells maximal transactivation levels were achieved in response to treatment with much lower E(2) concentrations (10(-10) M E(2)) when compared to MCF-7 control cells (10(-8) M E(2)). Furthermore, we have seen an increased association between ERalpha and its nuclear coactivators AIB1 or TIF-2, in MEK/MCF-7 cells relative to those seen in MCF-7 control cells. In addition, in vivo studies show that MEK/MCF-7 cell tumors are approximately threefold larger than those of MCF-7 cell, in the presence of E(2). Immunohistochemical staining demonstrates that progesterone receptor (PR) and pS2, two E(2)-regulated gene products, are significantly increased in MEK/MCF-7 cell tumors compared to those of MCF-7 control tumors, suggesting that activation of ERalpha by MAPK enhances the expression of E(2)-regulated genes and accelerates tumor growth. Remarkably, the antiestrogens tamoxifen and ICI 182,780, were shown both in vitro and in vivo studies to efficiently antagonize the stimulatory effects of E(2) on ER regulated transactivation and tumor growth in MEK/MCF-7 as well as MCF-7 cell lines. Taken together, these data suggest that MAPK/ER cross-talk enhances ERalpha-mediated signaling and accelerates E(2)-dependent tumor growth without diminishing sensitivity to the inhibitory effects of anti-estrogens.
...
PMID:MAP kinase/estrogen receptor cross-talk enhances estrogen-mediated signaling and tumor growth but does not confer tamoxifen resistance. 1203 82

LCoR (ligand-dependent corepressor) is a transcriptional corepressor widely expressed in fetal and adult tissues that is recruited to agonist-bound nuclear receptors through a single LXXLL motif. LCoR binding to estrogen receptor alpha depends in part on residues in the coactivator binding pocket distinct from those bound by TIF-2. Repression by LCoR is abolished by histone deacetylase inhibitor trichostatin A in a receptor-dependent fashion, indicating HDAC-dependent and -independent modes of action. LCoR binds directly to specific HDACs in vitro and in vivo. Moreover, LCoR functions by recruiting C-terminal binding protein corepressors through two consensus binding motifs and colocalizes with CtBPs in the nucleus. LCoR represents a class of corepressor that attenuates agonist-activated nuclear receptor signaling by multiple mechanisms.
...
PMID:Ligand-dependent nuclear receptor corepressor LCoR functions by histone deacetylase-dependent and -independent mechanisms. 1253 28

The differential expression pattern of estrogen receptor alpha (ER-alpha), estrogen receptor beta (ER-beta) and their co-activator/co-repressor proteins is thought to modulate estrogenic action and to be present already during the early stages of tumorigenesis. It has therefore been postulated that certain co-activator and co-repressor proteins contribute to the development of breast cancer. There are some reports providing information on gene amplification and mRNA over-expression of certain co-factors in breast cancer, but to date there is only limited knowledge about their respective protein expressions. The aim of this study was to examine the expression of four steroid receptor co-activators (steroid receptor co-activator 1 (SRC-1), transcription intermediary factor 2 (TIF 2), protein 300 kDa/CREB binding protein (p300/CBP), amplified in breast cancer 1 (AIB1)), and of the co-repressor nuclear receptor co-repressor (NCoR), in malignant breast tissues and in matching normal breast biopsies of the same individuals. Protein expression was analyzed by immunohistochemistry and was compared to prognostic parameters such as lymph node involvement, tumor grading and receptor status. All members of the co-regulatory protein family were detected in both, benign and matching malignant tissue samples, except for AIB1, which was found to be expressed exclusively in malignant epithelium. AIB1 was preferentially present in carcinomas with high tumor grade (r = 0.48, p = 0.014), and was co-expressed with p300/CBP (r = 0.54, p = 0.006). TIF 2 correlated significantly to nodal status (r = 0.46, p = 0.025). Furthermore, protein levels of ER-beta p300/CBP and AIB1 were higher in invasive ductal carcinomas than in normal mammary tissue. The tumoral ER-alpha protein expression was significantly correlated with that of PgR (r = 0.61, p = 0.001) and NCoR (r = 0.4, p = 0.043), whereas ER-beta expression was associated with SRC-1 (r = 0.68, p < or = .001), TIF 2 (r = 0.64, p = 0.001) and NCoR (r = 0.48, p = 0.014) protein levels in malignant specimens. In our hands, 20% of ER-beta positive tumors did not express ER-alpha protein, thereby suggesting that a substantial fraction of ER-beta positive tumors is falsely considered to be 'estrogen receptor negative' if only ER-alpha specific antibodies are employed in the histological assessment of the ER status.
...
PMID:Expression of sex steroid receptors and their co-factors in normal and malignant breast tissue: AIB1 is a carcinoma-specific co-activator. 1272 19

The ErbB-driven autocrine growth pathway has been implicated in the development and progression of most common human epithelial malignancies; its blockade is therefore a promising therapeutic strategy, and several candidate drugs are currently undergoing clinical trials. Paradoxically, little is known of the expression pattern of these 4 genes in human tumors, and the clinical significance of the 2 most recently discovered ERBB genes, ERBB3 and ERBB4, is unclear. We used a real-time quantitative RT-PCR assay to quantify ERBB family mRNA copy numbers in a large series of breast tumors from patients with known long-term outcome. ERBB gene expression varied widely, by more than 2 orders of magnitude for ERBB1 and ERBB3, more than 3 orders for ERBB2 and more than 4 orders for ERBB4. We found a positive correlation between ERBB3 and ERBB4 mRNA levels, and a negative correlation between the expression of these 2 latter genes and that of ERBB1. Compared to normal breast tissue, ERBB1 was underexpressed (82.3% of tumors), ERBB2 (16.9%) and ERBB3 (46.2%) were overexpressed and ERBB4 was both underexpressed (24.6%) and overexpressed (29.2%). Links were also found between ERBB status on the one hand and Scarff-Bloom-Richardson (SBR) histopathological grade and estrogen receptor alpha (ERa) status on the other hand. Relapse-free survival (RFS) was shorter among patients with ERBB3-overexpressing tumors (p=0.0092) and longer among those with ERBB4-underexpressing tumors (p=0.0085) relative to patients with normal expression of the respective genes; in contrast, RFS was not significantly influenced by ERBB1 or ERBB2 mRNA status. Only ERBB4 status retained prognostic significance in Cox multivariate regression analysis (p=0.015). Our results point to the involvement of several ErbB-specific ligands (amphiregulin and neuregulin 1) and enzymes or adaptor molecules (PI3K, Src, Shc and Grb7) in the ErbB pathway dysregulation associated with breast cancer. These findings reveal a complex expression pattern of ERBB gene family members in breast tumors and suggest that it is this pattern of expression, rather than the expression of individual family members, that should be taken into account when evaluating antitumoral drugs designed to target these receptors.
...
PMID:Prognostic value of ERBB family mRNA expression in breast carcinomas. 1286 37

Clinical observations demonstrate that women with breast cancer often respond to subsequent endocrine manipulation after resistance to initial hormonal therapy develops. As a mechanistic explanation for these findings, we hypothesized that human breast tumors can adapt in response to the pressure exerted by endocrine therapy with development of hypersensitivity to estradiol. To understand the signaling pathways responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term deprivation of estradiol (LTED) causes adaptive hypersensitivity. Even though the estrogen receptor alpha (ERalpha) is markedly up-regulated in LTED cells, the enhanced responses to estradiol do not appear to involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found that ERalpha co-opts a classical growth factor pathway and induces rapid nongenomic effects that are enhanced in LTED cells. Estradiol binds to cell membrane-associated ERs, physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb2 and Sos, which result in the rapid activation of mitogen-activated protein kinase. These nongenomic effects of estradiol produced biological effects, as evidenced by Elk-1 activation and by morphological changes in cell membranes. The mechanistic pathways involved in adaptive hypersensitivity suggest that inhibitors of the mitogen-activated protein kinase and phosphatidylinositol-3-OH kinase pathways might prevent the development of adaptive hypersensitivity and allow more prolonged efficacy of endocrine therapies.
...
PMID:Adaptive hypersensitivity to estrogen: mechanism for sequential responses to hormonal therapy in breast cancer. 1473 89

Approximately 70% of human breast cancers are estrogen receptor alpha (ERalpha)-positive, but the origins of ERalpha-positive and -negative tumors remain unclear. Hormonal regulation of mammary gland development in mice is similar to that in humans; however, most mouse models produce only ERalpha-negative tumors. In addition, these mouse tumors metastasize at a low rate relative to human breast tumors. We report here that somatic mutations of p53 in mouse mammary epithelial cells using the Cre/loxP system leads to ERalpha-positive and -negative tumors. p53 inactivation under a constitutive active WAPCre(c) in prepubertal/pubertal mice, but not under MMTVCre in adult mice, leads to the development of ERalpha-positive tumors, suggesting that target cells or developmental stages can determine ERalpha status in mammary tumors. Importantly, these tumors have a high rate of metastasis. An inverse relationship between the number of targeted cells and median tumor latency was also observed. Median tumor latency reaches a plateau when targeted cell numbers exceed 20%, implying the existence of saturation kinetics for breast carcinogenesis. Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors. Thus, this tumor system reproduces many important features of human breast cancer and provides tools for the study of the origins of ERalpha-positive and -negative breast tumors in mice.
...
PMID:Somatic mutation of p53 leads to estrogen receptor alpha-positive and -negative mouse mammary tumors with high frequency of metastasis. 1515 Jan 7


1 2 3 4 5 6 7 8 9 Next >>

---