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:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regulation of estrogen receptor (ER) concentration is a key component in limiting estrogen responsiveness in target cells. Yet the mechanisms governing ER concentration in the lactotrope cells of the anterior pituitary, a major site of estrogen action, are undetermined. In this study, we used a lactotrope cell line, PR1, to explore regulation of ER protein by estrogen. Estrogen treatment resulted in an approximate 60% decrease in ER steady state protein levels. Suprisingly, the decline in ER protein was apparent within 1 h of estrogen treatment and occurred in the absence of protein synthesis and transcription. Direct regulation of ER protein was further confirmed by pulse chase analysis, which showed that ER protein half-life was shortened from greater than 3 h to 1 h in the presence of estrogen. The estrogen-induced degradation of ER protein could be prevented by pretreatment with peptide aldehyde inhibitors of proteasome protease whereas inhibitors of calpain and lysosomal proteases were ineffective. Inhibition of proteasome activity maintained ER protein at a level equivalent to control cells not stimulated with estrogen but increased estrogen-binding activity by 1.75-fold. Proteolytic regulation of ER by the proteasome is not limited to pituitary lactotrope cells but is also operational in MCF-7 breast cancer cells, suggesting that this may be a common regulatory pathway used by estrogen. These studies describe a nongenomic action of estrogen that involves nuclear ER: rapid proteolysis of ER protein via a proteasome-mediated pathway.
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PMID:Proteasome-mediated proteolysis of estrogen receptor: a novel component in autologous down-regulation. 1047 43

Estrogen contributes to the development of breast cancer through mechanisms that are not completely understood. Estrogen influences the function of immune effector cells, primarily through alterations in cytokine expression. Chemokines are proinflammatory cytokines that attract various immune cells to the site of tissue injury or inflammation, and activate many cell types, including T lymphocytes and monocytes. As an initial step toward ultimately determining whether regulation of chemokine expression and/or biological activity by estrogen could potentially be a contributing factor to the development and progression of mammary tumors, we evaluated the effect of estrogen on the expression of specific chemokines in murine mammary tissue. We also evaluated whether exposure of female mice to various chemokines could alter the growth of mammary tumors in the presence of estrogen. We report here that estrogen significantly decreases levels of the chemokines MIP-1alpha and MCP-1/JE in murine mammary tissue. Co-treatment with 4-hydroxytamoxifen partially reverses the suppressive effect of estrogen on MIP-1alpha levels. Estrogen increases the growth of CCL- 51 cell-based tumors in the mammary glands of female mice. Co-treatment with the chemokine MIP-1alpha or MCP- 1/JE substantially decreases the ability of estrogen to stimulate the formation of CCL-51 cell-based tumors. Our results show that estrogen might influence the bioactivity of specific chemokines through alteration of chemokine expression in mammary tissue, and further suggest that decreases in murine chemokines evoked by estrogen exposure could contribute to the promotion of mammary tumor growth.
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PMID:Estrogen decreases chemokine levels in murine mammary tissue: implications for the regulatory role of MIP-1 alpha and MCP-1/JE in mammary tumor formation. 1466 21

Estrogen has crucial roles in the proliferation of cancer cells in reproductive organs such as the breast and uterus. Estrogen-stimulated growth requires two estrogen receptors (ERalpha and ERbeta) which are ligand-dependent transcription factors. High expression of ERs is observed in a large population of breast tumors. In addition, the positive expression of ERs correlates with well-differentiated tumors, a favorable prognosis, and responsiveness to an endocrine therapy with anti-estrogen drugs in patients with breast cancer. Transcription activities of ERs can be regulated by interacting proteins such as coactivators and kinases as well as ligand-binding. Moreover, ER isoforms lacking an ability to transactivate are involved in breast cancer. Downstream target genes of ERs have important roles in mediating the estrogen action in breast cancer. We have isolated and characterized several novel estrogen-responsive genes to clarify the molecular mechanism of the estrogen action in target cells. Among these genes, the estrogen-responsive finger protein (Efp) was found to be highly expressed in breast cancer. Efp as a ubiquitin ligase (E3) is involved in the proteasome-dependent degradation of the 14-3-3sigma protein, one of cell cycle brakes, this degradation resulting in the promotion of breast cancer growth. A full understanding of the expression and function of ERs and their target genes could shed light on how estrogen stimulates the initiation and promotion of cancer, providing a new approach to diagnose and treat cancer.
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PMID:Estrogen receptors and their downstream targets in cancer. 1578 84

Estrogen promotes the proliferation of human breast epithelial cells by interacting with the estrogen receptor (ER). Physiological responses of cells to estrogen are regulated in part by degradation of the ER. Previous studies revealed that calmodulin binds directly to the ER, thereby enhancing its stability. Consistent with these findings, cell-permeable calmodulin antagonists dramatically reduced the number of ER in MCF-7 human breast epithelial cells. Here we investigated the molecular mechanism by which calmodulin attenuates ER degradation. MG132 and lactacystin, inhibitors of the ubiquitin-proteasome pathway, prevented the calmodulin antagonist CGS9343B from reducing the amount of ER in MCF-7 cells. In contrast, protease inhibitors afforded no protection. Moreover, CGS9343B enhanced ER ubiquitination. A point mutant ER construct that is unable to bind calmodulin, termed ERDeltaCaM, is ubiquitinated to a greater extent than wild type ER. The ubiquitin-protein isopeptide ligase E6-associated protein (E6AP) associated with and promoted the degradation of ER. The possible convergence of calmodulin and E6AP on ER degradation was examined. ERDeltaCaM bound E6AP with higher affinity than that of wild type ER. Moreover, calmodulin attenuated the in vitro interaction between ER and E6AP in a Ca(2+)-dependent manner. Collectively, our data reveal that E6AP is a component of ER degradation via the ubiquitin-proteasome pathway and that Ca(2+)/calmodulin modulates this degradation mechanism. These results have potential implications for the development of selectively targeted therapeutic agents for breast cancer.
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PMID:E6AP and calmodulin reciprocally regulate estrogen receptor stability. 1631 11

Estrogen, which has been strongly implicated in breast cancer, suppresses apoptosis in estrogen receptor (ER) positive MCF-7 breast cancer cells. Phospholipase D (PLD), which is commonly elevated in ER negative breast cancer cells, also suppresses apoptosis. Survival signals generated by both estrogen and PLD are dependent upon elevated Myc expression. We report here that estrogen- and PLD-induced increases in Myc expression are due to reduced turnover of Myc protein. Estrogen and PLD suppressed phosphorylation of Myc at Thr58--a site that targets Myc for degradation by the proteasome. The data provide a mechanism for elevated Myc expression in hormone-dependent and hormone-independent breast cancer.
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PMID:Myc stabilization in response to estrogen and phospholipase D in MCF-7 breast cancer cells. 1699 3

Estrogen has striking effects on immunity and inflammatory autoimmune conditions. One potential mechanism of estrogen-induced regulation of immunity and inflammatory autoimmune conditions is by altering the secretion of chemokines by lymphocytes, an aspect not well addressed thus far. We found that estrogen has marked, but differential, effects on the secretion of chemokines from activated splenocytes. Estrogen treatment significantly increased the secretion of MCP-1, MCP-5, eotaxin, and stromal cell-derived factor 1beta from Con A-activated splenocytes when compared with placebo-treated controls, and it had no effects on the levels of RANTES, thymus and activation-regulated chemokine, and keratinocyte-derived chemokine (KC) at 24 h. A kinetic analysis showed that chemokines tended to increase with stimulation time, but only MCP-1 and MCP-5 showed a biological trend of increasing in splenocytes from estrogen-treated mice, and KC was decreased significantly in estrogen-treated splenocytes at 18 h. Estrogen did not affect the protein levels of chemokine receptors CCR1 or CCR2 at 24 h. Estrogen-induced alterations in the levels of MCP-1 and MCP-5 are mediated, in part, by IFN-gamma, as estrogen treatment of IFN-gamma null mice, unlike wild-type mice, did not up-regulate these chemokines. However, addition of recombinant IFN-gamma resulted in markedly increased secretion of MCP-1 and MCP-5 only in the cells derived from estrogen-treated mice. These studies provide novel data indicating that estrogen may promote inflammatory conditions by altering the levels of chemokines, providing evidence for an additional mechanism by which estrogens can regulate inflammation.
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PMID:Estrogen selectively regulates chemokines in murine splenocytes. 1718 57

Estrogen drives both transcriptional activation and proteolysis of estrogen receptor alpha (ER alpha; encoded by ESR1). Here we observed variable and overlapping ESR1 mRNA levels in 200 ER alpha-negative and 50 ER alpha-positive primary breast cancers examined, which suggests important posttranscriptional ER alpha regulation. Our results indicate that Src cooperates with estrogen to activate ER alpha proteolysis. Inducible Src stimulated ligand-activated ER alpha transcriptional activity and reduced ER alpha t(1/2). Src and ER alpha levels were inversely correlated in primary breast cancers. ER alpha-negative primary breast cancers and cell lines showed increased Src levels and/or activity compared with ER alpha-positive cancers and cells. ER alpha t(1/2) was reduced in ER alpha-negative cell lines. In both ER alpha-positive and -negative cell lines, both proteasome and Src inhibitors increased ER alpha levels. Src inhibition impaired ligand-activated ER alpha ubiquitylation and increased ER alpha levels. Src siRNA impaired ligand-activated ER alpha loss in BT-20 cells. Pretreatment with Src increased ER alpha ubiquitylation and degradation in vitro. These findings provide what we believe to be a novel link between Src activation and ER alpha proteolysis and support a model whereby crosstalk between liganded ER alpha and Src drives ER alpha transcriptional activity and targets ER alpha for ubiquitin-dependent proteolysis. Oncogenic Src activation may promote not only proliferation, but also estrogen-activated ER alpha loss in a subset of ER alpha-negative breast cancers, altering prognosis and response to therapy.
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PMID:Src promotes estrogen-dependent estrogen receptor alpha proteolysis in human breast cancer. 1762 4

Estrogen-induced proliferation in estrogen receptor (ER)-positive breast cancer cells is primarily mediated through two distinct intracellular receptors, ER alpha and ER beta. Although tumor necrosis factor alpha (TNF alpha) and E2/ER alpha are known to exert opposing effects on cell proliferation in MCF-7 cells, the mechanism by which TNFalpha antagonizes E2/ER alpha-mediated cell proliferation is not well understood. The present study suggests that reduced cell survival in response to TNF alpha treatment in MCF-7 cells may be associated with the down-regulation of ER alpha protein. The decrease in ER alpha protein level was accompanied by an inhibition of ER alpha gene transcription. Cell viability was decreased synergistically by the combined treatment with ER alpha-siRNA and TNF alpha. Furthermore, pretreatment of cells with the PI3-kinase (PI3K)/Akt inhibitor, LY294002, markedly enhanced TNF alpha-induced down-regulation of the ER alpha protein, suggesting that the PI3K/Akt pathway might be involved in control of the ER alpha level. Moreover, down-regulation of ER alpha by TNF alpha was not inhibited in cells that were pretreated with the proteasome inhibitors, MG132 and MG152, which suggests that proteasome-dependent proteolysis does not significantly influence TNF alpha-induced down-regulation of ER alpha protein. In contrast, the effect of the PI3K/Akt inhibitor on ER alpha was blocked in cells that were treated with LY294002 in the presence of the proteasome inhibitors. Collectively, our findings show that the TNF alpha may partly regulate the growth of MCF-7 breast cancer cells through the down-regulation of ER alpha expression, which is primarily mediated by a PI3K/Akt signaling.
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PMID:TNF alpha-induced down-regulation of estrogen receptor alpha in MCF-7 breast cancer cells. 1848 65

Shikonin (SK) has been isolated and identified as a key bioactive component in an herbal plant, Shikon (gromwell). In this study, we investigated antiestrogen activity of SK in breast cancer cells. In human breast cancer cells, we observed that treatment with SK inhibits tumor cell growth in estrogen receptor alpha (ERalpha)-positive, but not ERalpha-negative breast cancer cells. Estrogen-dependent cell growth was inhibited by co-treatment with SK. A potential molecular mechanism by which SK inhibits estrogen action was explored. We found that SK has no effect on ERalpha mRNA expression, but decreases its protein level. This effect is associated with an increase in ubiquitinated ERalpha for degradation. Our results suggest that SK downregulates ERalpha protein through a proteasome-mediated pathway. We also found that the treatment with SK inhibits estrogen-induced estrogen response elements reporter gene activity. Furthermore, SK inhibits recruitment of ERalpha at the estrogen-dependent gene promoters, and subsequently suppresses gene expression. Finally, co-treatment with SK enhanced sensitivity of breast cancer cells to endocrine therapy. Collectively, our studies suggested that SK has a potential for antihormone therapy in ERalpha-positive breast cancer cells, and should serve as a target for new drug developments.
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PMID:A novel antiestrogen agent Shikonin inhibits estrogen-dependent gene transcription in human breast cancer cells. 1976 May 1

The ErbB2/3 heterodimer plays a critical role in breast cancer progression and in the development of endocrine resistance. EBP1, an ErbB3 binding protein, inhibits HRG-stimulated breast cancer growth, decreases ErbB2 protein levels and contributes to tamoxifen sensitivity. We report here that ectopic expression of EBP1 in Estrogen Receptor (ER) positive breast cancers that express ErbB2 at both high and low levels decreased ErbB2 protein levels. ErbB2 protein expression was also increased in mammary glands of Ebp1 knock out mice. To define the mechanism of ErbB2 down regulation, we examined the effects of EBP1 on ErbB2 mRNA levels, transcription of the ErbB2 gene and ErbB2 protein stability. We found that ectopic expression of EBP1 decreased steady state levels of endogenous ErbB2 mRNA in all cell lines tested. EBP1 overexpression decreased the activity of an ErbB2 promoter reporter in cells which overxpress ErbB2. However, reporter activity was unchanged or increased in cells which express low endogenous levels of ErbB2. We also found that ectopic expression of EBP1 accelerated ErbB2 protein degradation and enhanced ErbB2 ubiquitination in cells which express both low and high levels of ErbB2. Treatment with proteasome inhibitors prevented this decrease in ErbB2 protein levels. Ablation of EBP1 expression led to tamoxifen resistance that was abrogated by inhibition of ErbB2 activity. These results suggest that EBP1 inhibits expression of ErbB2 protein levels by multiple mechanisms and that EBP1's effects on tamoxifen sensitivity are mediated in part by its ability to modulate ErbB2 levels.
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PMID:The ErbB3 binding protein EBP1 regulates ErbB2 protein levels and tamoxifen sensitivity in breast cancer cells. 2037 46


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