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)

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a compound from cooked meat, is an established mammary gland carcinogen in female rats. Four doses of PhIP (150 mg/kg, p.o., once per day) were given to lactating Sprague-Dawley rats separated from their 10-day-old pups to initiate involution of the gland. Twenty-four hours after the last dose, apoptotic index in the mammary gland, as measured by the TUNEL assay, was significantly higher in the gland from control rats than in the PhIP-treated rats (4.757 +/- 1.066 versus 1.905 +/- 0.248%; P < 0.05). In comparison with controls, alveoli in the mammary gland of PhIP-treated rats were also visibly larger and contained more secretory epithelial cells. The expression of Bax, a stimulator of apoptosis, and Bcl-2, an inhibitor of apoptosis, were quantitated by western blotting. Accordingly, Bax expression was 2.7-fold higher in control rats, whereas Bcl-2 expression was 3.1-fold higher in PhIP-treated rats, both changes being statistically different (Student's t-test, P < 0.05). Immunohistochemistry further confirmed a lower expression of Bax and higher expression of Bcl-2 in secretory alveolar epithelial cells of the PhIP-treated mammary gland. The findings are consistent with the notion that exposure to PhIP retarded involution via partial inhibition of programmed cell death. To investigate possible mechanisms for the inhibitory effects of PhIP on mammary gland involution, serum levels of prolactin, an important hormone for the maintenance of lactation, were measured in virgin rats with regular estrous cycles given PhIP (150 mg/kg, p.o.) on the morning of diestrous. After one estrous cycle, on proestrous morning, serum prolactin levels were 1.3-fold higher after PhIP than after control vehicle (one-way ANOVA, Fisher LSD multiple comparison test, P < 0. 05). PhIP exposure during involution was associated with the induction of benign mammary tumors. Seven out of 12 rats developed fibroadenomas, and one developed a tubulopapillary carcinoma within 1 year of receiving PhIP administration during involution (150 mg/kg, p.o., once per day for 5 days), and a high-fat diet (23.5% corn oil). An increase in serum prolactin level and the effects on mammary gland apoptosis seen with PhIP may have implications for the mechanisms of carcinogenic targeting of PhIP to the mammary gland.
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PMID:2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) retards mammary gland involution in lactating Sprague-Dawley rats. 1038 5

Development and activation of immune cells are submitted to hormonal influences, as illustrated by the roles of corticosteroids in thymus, pregnancy-related estrogens in B-cell development, or prolactin (PRL) on T-cell generation and function. We have analyzed the putative role of PRL in B lymphopoiesis and differentiation. We chose as an experimental model the interleukin (IL)-3 dependent BaF-3 pro-B cell line, which was transfected with the rat long form of the PRL receptor (PRL-R) and transferred from IL-3- to PRL-enriched media. When stimulated with PRL, the PRL-R transfectants underwent some changes characteristic of B-cell differentiation: (a) IL-2R alpha chain became positively controlled by PRL; (b) antiapoptotic Bcl-2 protein was induced by PRL in a dose-dependent manner; and (c) transcription of the pre-B cell receptor encoding the lambda5 gene was strongly up-regulated. We attempted to evaluate the differentiation-promoting activity of PRL in more physiological conditions, and the presence of PRL-R in bone marrow B-cell precursors was revealed. Furthermore, PRL promoted significant expansions of defined B-lineage cell populations in short-term bone marrow cell cultures. These findings suggest that PRL, in collaboration with other cytokines and hormonal influences, modulates B-cell development.
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PMID:Influence of prolactin on the differentiation of mouse B-lymphoid precursors. 1047 Aug 58

The effect of TGF-beta1, an auto/paracrine antiproliferative and apoptogenic factor on Bax transcript level (RT-PCR), subcellular distribution of Bax protein (immunoelectron microscopy), Bcl-2 protein level and apoptotic cell number (flow cytometry with FITC-conjugated monoclonal anti-Bcl-2 antibody and DNA stained with DAPI) in HC11 mouse mammary epithelial cells was examined. TGF-beta1 increased Bax transcript level (evaluated by Bax mRNA/GAPDH mRNA ratio) and stimulated Bax protein movement from cytosol to organellar membranes, mainly mitochondrial, during 60 min. The new observation is the presence of Bax on channel membranes of Golgi apparatus and translocation of Bax from cytosol to the fibrous nucleoplasm via nuclear envelope pores (especially after 120 min. of cell exposure to TGF-beta1). Prolactin protected HC11 cells against TGF-beta1-induced PCD, which could occur at two levels: 1) TGF-beta1 expression, through the decrease of TGF-beta1 transcript content, and 2) Bax/Bcl-2 checkpoint, through down-regulation of Bax and up-regulation of Bcl-2. In conclusion, Bax and Bcl-2 proteins are implicated in the mechanism of TGF-beta1-induced PCD and antiapoptotic action of prolactin in HC11 mouse mammary epithelial cells. The activation of transcription and redistribution of Bax from cytosol to organellar membranes and nucleus constitute the early events in the cellular response to TGF-beta1.
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PMID:Expression and subcellular redistribution of Bax during TGF-beta1-induced programmed cell death of HC11 mouse mammary epithelial cells. 1072 83

Prolactin (PRL) inhibits apoptosis and stimulates proliferation of the PRL-dependent rat Nb2 lymphoma cell line by divergent signaling pathways. Nitric oxide (NO) was recently identified as a downstream regulator of PRL action, and as an inhibitor of apoptosis in immune cells. In the present study, the role of NO in PRL-regulated Nb2 cell function was investigated. Nb2 cells expressed the endothelial nitric oxide synthase (eNOS) isoform, whereas neuronal NOS (nNOS) and inducible NOS (iNOS) mRNAs were undetectable. The eNOS mRNA was abundantly expressed in PRL-deprived, growth-arrested cells but decreased by at least 3-fold at 3-24 h following PRL treatment. Downregulation of eNOS was not accompanied by a corresponding decrease in the eNOS protein, the level of which remained constant for at least 24 h after PRL treatment. PRL had no effect on the phosphorylation state or subcellular redistribution of the eNOS enzyme, or on production of NO by Nb2 cells. However, increasing concentrations of L-arginine (NOS substrate) alone increased NO production in these cells and significantly enhanced PRL-stimulated cell proliferation. NO releasers (SNAP, DEA/NO, SIN-1) also significantly enhanced Nb2 cell proliferation in the presence of a submaximal dose of PRL (0.125 ng/ml). In the absence of PRL, the NO releasers alone promoted cell survival and maintained a viable cell density significantly higher than that of untreated PRL-deprived cells. L-arginine or the NO releaser DEA/NO alone significantly inhibited apoptosis in Nb2 cells deprived of PRL for 5 days. Expression of the anti-apoptotic gene bcl-2, which was stimulated within 1 h by PRL, was upregulated by L-arginine or DEA/NO alone at 2 h and 8 h, respectively. These findings suggest that NO produced by eNOS inhibits apoptosis and promotes the survival of growth-arrested Nb2 lymphoma cells via a prolactin-independent, Bcl-2-mediated pathway.
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PMID:L-arginine inhibits apoptosis via a NO-dependent mechanism in Nb2 lymphoma cells. 1077 18

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

The effects of the polypeptide hormone prolactin (PRL) in the development and regulation of benign prostate hyperplasia (BPH) and also in prostate cancer are not very well characterized. This study examines the action of PRL, either alone or in association with androgens [testosterone (T) or dihydrotestosterone (DHT)], in the rat prostate gland. The effects of PRL and androgens were investigated after 30 and 60 days in control, castrated, castrated with a substitutive implant of T or DHT, and sham-operated Wistar rats. To enhance PRL release, we induced hyperprolactinemia by administering chronic injections of sulpiride (40 mg. kg(-1). day(-1)). Chronic hyperprolactinemia induces enlargement and inflammation of the lateral rat prostate without any histological changes on ventral and dorsal lobes. We also demonstrate that hyperprolactinemia induces Bcl-2 overexpression in the lateral rat prostate and that this could inhibit the level of apoptosis. The in vivo model established here is a useful in vivo approach for studying the hormonal regulation of normal and pathological prostate development.
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PMID:Effects of hyperprolactinemia on rat prostate growth: evidence of androgeno-dependence. 1112 Jun 66

The effect of a-difluoromethylornithine (DFMO) on the apoptosis of HC11 mouse mammary epithelial cells was investigated. The involvement of reactive oxygen species (ROS) and Bcl-2 protein in the mechanism of apoptosis induced by ornithine decarboxylase (ODC) inhibition was also assessed. DFMO (0.1, 1 and 5mM) induced apoptosis of HC11 cells in dose- and time-dependent manner. Apoptosis manifests itself with morphological features like: cell shrinkage, condensation of chromatin, pyknosis and fragmentation of nucleus, followed by secondary necrosis (putrosis). The decrease in the nuclear DNA contents appearing as the hypodiploidal peak sub-G1 in the DNA histogram was not dependent on the presence of prolactin (5 microg/ml) in DFMO-treated cultures. Apoptosis induced by ODC inhibition was associated with a rapid increase in ROS concentration in HC11 cells observed within 1 h after DFMO treatment. The down-regulation of Bcl-2 as a decrease in cell number expressing bcl-2 and a lowered Bcl-2 protein content in cells expressing this protooncogene was also noted. The administration of putrescine (50 microM) lowered the number of early-apoptotic, late-apoptotic and necrotic cells. Moreover, it increased the number of cells expressing bcl-2. In conclusion, the disturbance of cellular polyamine homeostasis by inhibition of their synthesis enhances mammary epithelial cell susceptibility to apoptosis. It may occur in the mammary gland at the end of lactation, when the depletion of circulating lactogenic hormones and activation of intra-mammary apoptogenic factors expression take place.
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PMID:Inhibition of ornithine decarboxylase by alpha-difluoromethylornithine induces apoptosis of HC11 mouse mammary epithelial cells. 1112 55

In a companion article, we describe the engineering and characterization of pituitary GH3 cell clones stably transfected with a furin-cleavable human insulin cDNA (InsGH3 cells). This article describes the performance of InsGH3 (clones 1 and 7) cell grafts into streptozotocin (STZ)-induced diabetic nude mice. Subcutaneous implantation of 2 x 10(6) InsGH3 cells resulted in the progressive reversal of hyperglycemia and diabetic symptoms, even though the progressive growth of the transplanted cells (clone 7) eventually led to glycemic levels below the normal mouse range. Proinsulin transgene expression was maintained in harvested InsGH3 grafts that, conversely, lose the expression of the prolactin (PRL) gene. Elevated concentrations of circulating mature human insulin were detected in graft recipients, demonstrating that proinsulin processing by InsGH3 cells did occur in vivo. Histologic analysis showed that transplanted InsGH3 grew in forms of encapsulated tumors composed of cells with small cytoplasms weakly stained for the presence of insulin. Conversely, intense insulin immunoreactivity was detected in graft-draining venules. Compared to pancreatic betaTC3 cells, InsGH3 cells showed in vitro a higher rate of replication, an elevate resistance to apoptosis induced by serum deprivation and proinflammatory cytokines, and significantly higher antiapoptotic Bcl-2 protein levels. Moreover, InsGH3 cells were resistant to the streptozotocin toxicity that, in contrast, reduced betaTC3 cell viability to 50-60% of controls. In conclusion, proinsulin gene expression and mature insulin secretion persisted in transplanted InsGH3 cells that reversed hyperglycemia in vivo. InsGH3 cells might represent a potential beta-cell surrogate because they are more resistant than pancreatic beta cells to different apoptotic insults and might therefore be particularly suitable for encapsulation.
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PMID:Insulin-secreting pituitary GH3 cells: a potential beta-cell surrogate for diabetes cell therapy. 1120 70

Evidence accumulated over the last two decades indicates important actions for prolactin (PRL) in regulation of several functions of the immune system. That PRL can serve to facilitate immune cell proliferation is well established. In addition, PRL appears to play a salient role in the genesis and/or potentiation of certain autoimmune diseases. Recent evidence from several laboratories has extended the spectrum of PRL actions in immunological systems to include regulation of lymphocyte pool size through the process of apoptosis. Experimental results obtained using lactogen-dependent rat pre-T cell lines, the Nb2 lymphoma, have demonstrated that PRL suppresses cell death mechanisms activated by cytokine/hormone deprivation and cytotoxic drugs such as glucocorticoids. In this paper, we review results from studies conducted to investigate the mechanism(s) underlying PRL-regulated apoptosis suppression. Effects of the hormone on expression of apoptosis-associated genes of the Bcl-2 family as well as the protooncogene pim-1 in proliferating Nb2 sublines and in cells exposed to apoptotic stimuli are presented. It is concluded that PRL-mediated apoptosis suppression in immune cells reflects a complex interaction among several gene products.
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PMID:Prolactin regulation of apoptosis-associated gene expression in T cells. 1126 80

The expression of apoptosis-related proteins: TGF-beta1 (auto/paracrine inducer) and its receptor (TGF-betaRIII), Bax (promoter), Bcl-2 (inhibitor) and CPP-32 (executor of apoptosis) as well as the apoptotic cell number in mammary glands of 11 Polish White Improved goats in the course of the lactation cycle (peak of lactation: days 40-70, late lactation: days 208-256, drying off: days 267-340) was investigated. The immunohistochemical study demonstrated a significant increase in TGF-beta1 and TGF-betaRIII expression in the lobuloalveolar tissue from the early lactation to the dry period. Our recent study on HC11 mouse mammary epithelial cells [Cell. Mol. Biol. 46 (2000) 175] has revealed an inhibitory effect of prolactin on TGF-beta1 transcription, which may explain the low TGF-beta1 synthesis during lactogenesis and galactopoiesis and the increase in TGF-beta1 and TGF-betaIIIR expression in late lactation and dry period. Bax expression was the lowest in the peak of lactation, significantly increased in late lactation and remained elevated during drying off. Bcl-2 content was lower than Bax in all examined periods, but it increased significantly at the end of lactation, which suggests the survival of cells with the highest resistance to apoptogenic stimuli. The increase in Bcl-2 level in remnant lobuloalveolar tissue is probably the molecular mechanism that limits the rate of secretory tissue involution. The induction of CPP-32 (caspase 3) from the peak of lactation to dry period was accompanied by a progressive loss of mammary epithelial cells and the increase in apoptotic cell numbers but only in the dry period. The increase in the expression of examined proteins in the late lactation and the dry period indicates their involvement in the induction (TGF-beta1 and TGF-betaRIII), regulation (Bax and Bcl-2) and execution (CPP-32) of programmed cell death in the course of mammary gland involution. The lack of an increase in apoptotic cell number in late lactation, in spite of the evident decrease in total cell number, suggests milk as an alternative route (apart from phagocytosis) of apoptotic cells elimination from the mammary gland. The presented results provide new insights into the molecular mechanism of mammary cell apoptosis in goat and for this reason may have practical implications for control and regulation of mammary gland remodelling, which is a prerequisite for subsequent successful lactation.
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PMID:Expression of apoptosis-related proteins in mammary gland of goat. 1132 13


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