Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that the Bcl-2 protein suppresses programmed cell death or apoptosis induced by a variety of stimuli including chemotherapeutic drugs. Because estrogen promotes the survival of estrogen-dependent breast cancer cells in vivo, we investigated whether estrogen might regulate levels of Bcl-2 gene expression in an estrogen-responsive human breast cancer cell line. Estrogen receptor-positive MCF-7 human breast cancer cells cultured in the presence of estrogen express the 8.5-kb Bcl-2 mRNA transcript. Depletion of estrogen from the medium results in loss of expression of the mRNA, whereas reexposure to estrogen markedly induces the Bcl-2 transcript. The changes in Bcl-2 mRNA are paralleled by changes in Bcl-2 protein levels. Estrogen-induced increases in Bcl-2 are significantly inhibited by inclusion of the pure antiestrogen ICI 164,384 in the medium. The Bax protein that heterodimerizes with Bcl-2 and promotes cell death is expressed in MCF-7 cells grown in the presence of estrogen and is unaffected by culture in estrogen-free medium. Estrogen depletion doubles the sensitivity of MCF-7 cells to the cytotoxic effects of Adriamycin compared with cells cultured in medium supplemented with estrogen, consistent with a decrease in the Bcl-2 levels. MCF-7 cells treated simultaneously with estrogen and ICI 164,384 exhibit markedly lower resistance to Adriamycin compared with cells treated with estrogen alone. In the absence of estrogen, MCF-7 cells transfected with Bcl-2 expression plasmids display a marked increase in resistance to Adriamycin. In the presence of estrogen, MCF-7 cells expressing Bcl-2 antisense transcripts are rendered twice as sensitive to acute Adriamycin cytotoxicity as a control clone. We conclude that estrogen can promote resistance of estrogen receptor bearing human breast cancer cells to chemotherapeutic drugs through a mechanism that involves regulation of the Bcl-2 proto-oncogene.
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PMID:Estrogen promotes chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human breast cancer cells. 764 Dec 10

Uterine leiomyoma is the most common smooth muscle cell tumor of the myometrium. Estrogen and progesterone (P4) are believed to be physiological regulators of leiomyoma growth. We recently showed that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to its expression in the normal myometrium and that Bcl-2 protein expression in cultured leiomyoma cells was up-regulated by P4, but down-regulated by 17 beta-estradiol (E2). To further characterize the molecular mechanism of sex steroidal regulation of leiomyoma growth, we examined the effect of menstrual phase on proliferating cell nuclear antigen (PCNA) expression in leiomyoma and investigated whether sex steroids could influence PCNA expression in leiomyoma cells cultured under serum-free conditions by immunoblot and immunohistochemical analyses. As epidermal growth factor (EGF) has been shown to mediate estrogen action and to play a crucial role in regulating leiomyoma growth, we also investigated the effects of sex steroids on the expression of EGF and EGF receptor (EGF-R) in cultured leiomyoma cells. The PCNA labeling index in leiomyomas was much greater in the secretory, P4-dominated, phase than in the proliferative phase of the menstrual cycle and was significantly higher than that in the adjacent normal myometrium throughout the menstrual cycle. In monolayer cultures of leiomyoma cells, the addition of either E2 (10 ng/mL) or P4 (100 ng/mL) resulted in an increase in PCNA expression in the cells compared to that in control cultures, whereas in monolayer cultures of myometrial cells, the addition of E2 augmented PCNA expression in the cells, but P4 did not. Immunoblot analysis of proteins extracted from cultured leiomyoma cells revealed that leiomyoma cells contained immunoreactive EGF with a molecular mass of 133 kDa and that the addition of P4 resulted in a remarkable increase in the expression of 133- and 71-kDa immunoreactive EGF in the cells compared to that in control cultures, whereas the addition of E2 resulted in a somewhat lower expression of immunoreactive EGF in the cells. Furthermore, immunocytochemical analysis with a monoclonal antibody to human EGF-R demonstrated that the treatment with E2 augmented EGF-R expression in the cells compared to that in untreated cells, but P4 did not. The concentrations of sex steroids used were within the physiological tissue concentrations found in leiomyomas and myometria. These results indicate that P4 up-regulates the expression of PCNA and immunoreactive EGF in leiomyoma cells, whereas E2 up-regulates the expression of PCNA and EGF-R in those cells. As it is evident that EGF plays a crucial role as a local factor in regulating leiomyoma growth, the P4-induced increase in PCNA expression in leiomyoma cells may be mediated by P4-induced enhanced expression of EGF-like proteins in the cells, whereas the E2-induced increase in PCNA expression in leiomyoma cells may be mediated by E2-induced enhanced expression of EGF-R in those cells. It is, therefore, conceivable that P4 and E2 act in combination to stimulate the proliferative potential of leiomyoma cells through the induction of EGF-like proteins and EGF-R expression in uterine leiomyoma.
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PMID:Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma. 962 59

The ability of estrogen to prevent glucocorticoid-induced apoptosis in osteoblasts was studied both in vitro and in vivo. Glucocorticoid treatment for 72 h produced a dose-dependent increase in the number of apoptotic cells, determined by acridine orange/ethidium bromide staining, with a maximal response of 31+/-2% and 26+/-3% with 100 nM corticosterone in primary rat and mouse osteoblasts, respectively. Simultaneous administration of varying concentrations of 17beta-estradiol and 100 nM corticosterone decreased apoptotic osteoblasts in a dose-dependent manner, with a maximal decrease of 70% with 0.01 nM 17beta-estradiol. Terminal deoxynucleotidyltransferase-mediated deoxy-UTP-biotin nick end labeling also demonstrated glucocorticoid-induced DNA fragmentation that was inhibited by estrogen. Estrogen was shown to inhibit apoptosis induced by lipopolysaccharide treatment. As early as 6 h, Western blots demonstrated a dose-dependent decrease in the Bcl-2/Bax ratio, which reached a minimum of 0.18 in osteoblasts treated with 1000 nM corticosterone for 72 h. This reduction in Bcl-2/Bax was abolished by treating osteoblasts simultaneously with 17beta-estradiol, but not with 17alpha-estradiol. In 7-day-old mice, administration of varying concentrations of dexamethasone for 72 h resulted in a dose-dependent increase in the number of apoptotic osteoblasts as demonstrated by in situ terminal deoxynucleotidyltransferase-mediated deoxy-UTP-biotin nick end labeling staining of calvaria. A maximum of 22+/-1% apoptotic osteoblasts on the bone surface was found with 1 mg/kg BW dexamethasone compared with 2+/-1% in vehicle-treated mice. Injection of varying concentrations of 17beta-estradiol (0.5-5 mg/kg BW), but not 17alpha-estradiol, with 1 mg/kg dexamethasone produced a dose-dependent decrease in the number of apoptotic osteoblasts to 5+/-1% with 5 mg/kg 17beta-estradiol. Thus, glucocorticoid-induced apoptosis of osteoblasts may be prevented at least in part by 17beta-estradiol.
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PMID:Estrogen prevents glucocorticoid-induced apoptosis in osteoblasts in vivo and in vitro. 1053 65

Sex hormones are presumed to contribute to sexual dimorphism in the immune system. Estrogen, in particular, has been suggested to predispose women to systemic lupus erythematosus. We report here that estradiol (E(2)) can break B cell tolerance and induce a lupus-like phenotype in nonautoimmune mice transgenic for the heavy chain of a pathogenic anti-DNA antibody. E(2) treatment resulted in a rise in anti-DNA serum titers and in Ig deposition in renal glomeruli. ELISPOT analysis confirmed a significant increase in the number of high-affinity anti-DNA antibody-secreting B cells in the spleens of E(2)-treated mice. Hybridomas generated from E(2)-treated mice express high-affinity, unmutated anti-DNA antibodies, indicating that naive B cells that are normally deleted or anergized are rescued from tolerance induction. Finally, immunohistochemical studies revealed increased Bcl-2 expression in splenic B cells of E(2)-treated mice. These data demonstrate that estrogen interferes with tolerance induction of naive autoreactive B cells and that the presence of these B cells in the periphery is associated with up-regulation of Bcl-2.
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PMID:Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. 1069 76

B lymphocyte production in murine bone marrow is negatively regulated by sex steroids and the aim of this study was to identify early hormone sensitive checkpoints. Estrogen (E2) treatment reduced cmu(+) pre-B cells, a change that occurred concomitantly with decreased Ig gene rearrangements and rag-1 transcripts. Estrogen decreased B lineage precursors in Ig transgenic mice, demonstrating that hormonal regulation is independent of the recombination process. B lineage precursors in Bcl-2 transgenic mice were resistant to estrogen treatment, suggesting that life/death decisions are involved in hormonal regulation. A previously uncharacterized population of CD43(-)cmu(-) B lineage precursors was identified in normal, Ig transgenic, and RAG(-/-) mice after estrogen treatment, revealing that down-regulation of CD43 can occur independent of Ig heavy chain expression. These cells expressed transcripts for both tdt and bcl-2, characteristics of early B-cell precursors. BrdU incorporation analysis revealed that the mitotic activity of early B-lineage cells is reduced in hormone-treated mice. We conclude that sex steroids modulate the production of B-lineage cells by influencing the differentiation, proliferation, and survival of early B-cell precursors. These findings are informative about mechanisms of hormonal regulation, as well as the significance of some differentiation-related events. (Blood. 2000;95:2059-2067)
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PMID:Estrogen influences the differentiation, proliferation, and survival of early B-lineage precursors. 1070 75

Understanding the process of carcinogenesis is key to developing therapies which might interrupt or reverse tumor onset and progression. Cell growth and death signals are dependent not only upon molecular mechanisms within a cell but also upon external stimuli such as hormones, cell - cell signaling, and extracellular matrix. Mouse models can be used to dissect these complex processes, to identify key signaling pathways operating at different stages of tumorigenesis, and to test the strength of specific interventions. In the WAP-TAg mouse model, carcinogenesis is initiated by expression of the Simian Virus 40 T antigen (TAg). TAg expression is triggered by hormonal stimulation, either during estrus or pregnancy. Breast adenocarcinomas (ranging from well to poorly differentiated) develop in 100% of the female mice by approximately 8 - 9 months of age. Three distinct stages of tumorigenesis are easily identified: an initial proliferation, hyperplasia, and adenocarcinoma. The mean time to first palpable tumor in mice which undergo at least one pregnancy is 6 months. The tumorigenic process is marked by a competition between proliferation and apoptosis and is characterized by cellular acquisition of genetic mutations and increased stromal fibrosis. Protein levels of cell cycle control genes cyclin D1, cdk2, and E2F-1 are increased in these adenocarcinomas. c-Fos protein levels are slightly increased in these cancers, while c-Jun levels do not change. Hormonal exposure alters progression. Estrogen plays a role during the early stages of oncogenesis although the growth of the resulting adenocarcinomas is estrogen-independent. Transient hormonal stimulation by glucocorticoids that temporarily increases the rate of cell proliferation results in tetraploidy, premature appearance of irreversible hyperplasia, and early tumor development. Tumor appearance also can be accelerated through over expression of the cell survival protein, Bcl-2. Bcl-2 over expression not only reduces apoptosis during the initial proliferative process but also decreases the total rate of cell proliferation. This block in cell proliferation is lost selectively as the cells transition to adenocarcinoma. The WAP-TAg model can be utilized to investigate how the basic processes of cell proliferation, apoptosis, DNA mutation, and DNA repair are modified by external and internal signals during mammary oncogenesis.
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PMID:WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis. 1071 84

Estrogen can modulate autoimmunity in certain models of systemic lupus erythematosus. Recently, we have shown that it can mediate survival and activation of anti-DNA B cells in a mouse transgenic for the heavy chain of a pathogenic anti-DNA antibody. To identify whether estrogen effects reflect increased prolactin secretion, we characterized B-cell autoreactivity in transgenic mice given both bromocriptine (an inhibitor of prolactin secretion) and estradiol. Treatment of mice with estradiol plus bromocriptine led to reduced titers of anti-DNA antibodies and diminished IgG deposition in kidneys compared with treatment with estradiol alone. However, mice treated with estradiol plus bromocriptine showed an expansion of transgene-expressing B cells and enhanced Bcl-2 expression, similar to those of estradiol-treated mice. We identified anergic high-affinity anti-DNA B cells in mice treated with estradiol plus bromocriptine, and we showed by molecular analysis of anti-DNA hybridomas that their B cells derive from a naive repertoire. Thus, the estradiol-induced breakdown in B-cell tolerance can be abrogated by bromocriptine, which induces anergy in the high-affinity DNA-reactive B cells. These studies demonstrate that some of the effects of estrogen on naive autoreactive B cells require the presence of prolactin and, thus, suggest potential therapeutic interventions in lupus.
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PMID:Bromocriptine restores tolerance in estrogen-treated mice. 1110 90

Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ERalpha in the absence of estrogen. Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERalpha, AKT increased the activity of only AF-1. PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKT-dependent and AKT-independent pathways in activating ERalpha. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ERalpha in vivo. Moreover, AKT overexpression led to up-regulation of estrogen-regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate that AKT protects breast cancer cells from tamoxifen-induced apoptosis. Taken together, these results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERalpha, and inhibition of tamoxifen-induced apoptotic regression.
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PMID:Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. 1113 88

Estrogen replacement therapy in menopausal women has been suggested to be beneficial in preventing the progression of cognitive impairment in Alzheimer disease. We demonstrated previously that the phosphatidylinositol 3-kinase (PI3-K)/Akt signal transduction pathway plays a pivotal role on the neuroprotection provided by 17beta-estradiol against acute glutamate toxicity. In the present study, we investigated the mechanism of neuroprotection against apoptosis because acute glutamate toxicity predominantly induced necrosis. 17beta-estradiol provided neuroprotection against apoptosis induced by staurosporine. This neuroprotection was inhibited by pretreatment with a PI3-K inhibitor, LY294002. An estrogen receptor specific antagonist, ICI182780, also suppressed the neuroprotection provided by 17beta-estradiol. Western blotting analysis demonstrated that treatment with 17beta-estradiol induced the phosphorylation of Akt within 5 min, which was suppressed by pretreatment with LY294002 and ICI182780. Furthermore, 17beta-estradiol induced phosphorylation of the cAMP response element binding protein (CREB) at Ser(133) within 15 min and then upregulated Bcl-2 in a PI3-K/Akt-dependent manner. Because CREB is known to be a transcription factor for Bcl-2, these results suggest that 17beta-estradiol exerts its antiapoptotic effects by CREB phosphorylation and Bcl-2 upregulation via nongenomic activation of the PI3-K/Akt pathway in cultured cortical neurons.
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PMID:Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. 1139 1

Data from epidemiological studies suggest that the decline in estrogen following menopause could increase the risk of neurodegenerative diseases. Furthermore, experimental studies on different animal models have shown that estrogen is neuroprotective. The mechanisms involved in the neuroprotective effects of estrogen are still unclear. Anti-oxidant effects, activation of different membrane-associated intracellular signaling pathways, and activation of classical nuclear estrogen receptors (ERs) could contribute to neuroprotection. Interactions with neurotrophins and other growth factors may also be important for the neuroprotective effects of estradiol. In this review we focus on the interaction between insulin-like growth factor-I (IGF-I) and estrogen signaling in the brain and on the implications of this interaction for neuroprotection. During the development of the nervous system, IGF-I promotes the differentiation and survival of specific neuronal populations. In the adult brain, IGF-I is a neuromodulator, regulates synaptic plasticity, is involved in the response of neural tissue to injury and protects neurons against different neurodegenerative stimuli. As an endocrine signal, IGF-I represents a link between the growth and reproductive axes and the interaction between estradiol and IGF-I is of particular physiological relevance for the regulation of growth, sexual maturation and adult neuroendocrine function. There are several potential points of convergence between estradiol and IGF-I receptor (IGF-IR) signaling in the brain. Estrogen activates the mitogen-activated protein kinase (MAPK) pathway and has a synergistic effect with IGF-I on the activation of Akt, a kinase downstream of phosphoinositol-3 kinase. In addition, IGF-IR is necessary for the estradiol induced expression of the anti-apoptotic molecule Bcl-2 in hypothalamic neurons. The interaction of ERs and IGF-IR in the brain may depend on interactions between neural cells expressing ERs with neural cells expressing IGF-IR, or on direct interactions of the signaling pathways of alpha and beta ERs and IGF-IR in the same cell, since most neurons expressing IGF-IR also express at least one of the ER subtypes. In addition, studies on adult ovariectomized rats given intracerebroventricular (i.c.v.) infusions with antagonists for ERs or IGF-IR or with IGF-I have shown that there is a cross-regulation of the expression of ERs and IGF-IR in the brain. The interaction of estradiol and IGF-I and their receptors may be involved in different neural events. In the developing brain, ERs and IGF-IR are interdependent in the promotion of neuronal differentiation. In the adult, ERs and IGF-IR interact in the induction of synaptic plasticity. Furthermore, both in vitro and in vivo studies have shown that there is an interaction between ERs and IGF-IR in the promotion of neuronal survival and in the response of neural tissue to injury, suggesting that a parallel activation or co-activation of ERs and IGF-IR mediates neuroprotection.
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PMID:Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection. 1174 97


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