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)

In rapidly proliferating tissues the stringent control of cell proliferation and cell death by apoptosis is central to the maintenance of tissue homeostasis. In the gastrointestinal tract most work studying the control of tissue cell number has traditionally focused on the growth factor control of proliferation, and the changes that occur during carcinogenesis. However, in recent years it has become increasingly apparent that the control of apoptosis is also crucial. Apoptosis is an important mechanism for eliminating both excess normal cells and those cells which have sustained damage; therefore maintaining a tissue, i.e., stem cells with preserved DNA integrity. In this review the incidence of apoptosis in the stem cells of both the small and large intestine will be discussed in relation to the expression of a number of apoptosis regulating genes (e.g. p53, Bcl-2, bax) within these cells. The importance of apoptosis as a means of controlling stem cell number (and therefore cellular output) will be addressed, as will the mechanisms by which any alterations to this process may contribute to malignancy.
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PMID:Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. 909 Jul 84

The intracellular balance between pro- and antiapoptotic members of the Bcl-2 gene family is thought to regulate cell death. Targeted disruption of bcl-x, a death repressing member, causes massive cell death of immature neurons in the developing mouse CNS, whereas targeted disruption of bax, a proapoptotic member, blocks the death of specific populations of sympathetic and motor neurons. In the present study, mice deficient in both Bcl-xL and Bax (bcl-x-/-/bax-/-) are used to examine the relative significance and potential interactions of Bcl-xL and Bax during early CNS development. bcl-x-/-/bax-/- mice demonstrate greatly reduced levels of apoptosis both in vivo and in vitro compared with the CNS of Bcl-xL-deficient mice, as assessed by histology and terminal deoxytransferase-mediated deoxyuridine triphosphate nick end-labeling. Bax-deficient mice, however, contain occasional apoptotic cells in the developing CNS, and cultures of bax-deficient telencephalic cells demonstrate similar levels of apoptosis as wild-type cultures. These results suggest that Bax critically interacts with Bcl-xL to regulate survival of immature neurons, but indicate that other cell death regulating proteins, in addition to Bcl-xL and Bax, also function during CNS development.
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PMID:Bax deficiency prevents the increased cell death of immature neurons in bcl-x-deficient mice. 909 45

In the Syrian hamster, neonatal diethylstilbestrol (DES) treatment and then postpubertal estrogen stimulation induces hyperplasia plus apoptosis (preneoplastic responses) and ultimately neoplasia in the endometrial epithelial cell compartment. As part of a project to investigate the molecular and cellular mechanisms responsible for this phenomenon, expression of several proto-oncogenes (c-jun, c-fos, c-myc, bax, bcl-2 and bcl-x) was compared in estrogen-stimulated uteri from control versus neonatally DES-treated hamsters. According to Northern blot analysis of total uterine RNA, levels of the 3.2-kb c-jun and 2.4-kb c-myc transcripts were not altered by neonatal DES treatment. However, the 1.0 kb bax and 2.7 kb bcl-x transcript levels were significantly increased in the neonatally DES-exposed uteri. According to immunohistochemical analysis of paraformaldehyde-fixed and paraffin-embedded tissue sections, levels of c-Jun, c-Fos, c-Myc, Bax, and Bcl-x proteins were enhanced dramatically in both the luminal and glandular epithelial cells of neonatally DES-exposed uteri. In contrast, the immunostaining signal for Bcl-2 protein was decreased consistently in the epithelial cells of neonatally DES-exposed uteri. In conclusion, neonatal DES treatment induced persistent and epithelial cell-specific imbalances in the estrogen-regulated uterine expression of c-jun, c-fos, c-myc, bax, bcl-2, and bcl-x proto-oncogenes. These imbalances likely play a role in the molecular mechanism by which neonatal DES treatment induces altered estrogen responsiveness including hyperplasia, apoptosis, and ultimately neoplasia in the epithelial compartment of the hamster uterus.
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PMID:Neonatal diethylstilbestrol treatment alters the estrogen-regulated expression of both cell proliferation and apoptosis-related proto-oncogenes (c-jun, c-fos, c-myc, bax, bcl-2, and bcl-x) in the hamster uterus. 910 Oct 88

CD6 and CD5 belong to a scavenger-receptor cysteine-rich (SRCR) super family of membrane glycoproteins that are expressed on chronic lymphocytic leukemia B (B-CLL) cells, normal T cells, and a small subset of normal B cells. CD6 configures in the membrane in relation to the cellular activation level and can act as a coreceptor for T-cell activation. We have examined a group of progressive and nonprogressive B-CLL cells. Most B-CLL cells were positive for CD6 and the expression of CD6 was increased after activation with Staphylococcus aureus Cowan I plus interleukin-2 or 12-O-tetradecanoylphorbol 13-acetate, although anti-CD6 antibodies did not increase proliferative responses to these stimuli. However, anti-CD6 stimulation was found to protect against anti-IgM-induced apoptosis in B-CLL. bax(alpha) upregulation and bcl-2 downregulation were found in anti-IgM- and glucocorticoid (GCC)-induced apoptotic cells, respectively. Furthermore, CD6 cross-linking downregulated bax(alpha) mRNA levels in anti-IgM-treated cells, resulting in an increased bcl-2/bax(alpha) ratio. CD6 activation also prevented bcl-2 mRNA downregulation and apoptosis induced by GCC in one of six GCC-sensitive patients. These data suggest that an interaction between CD6 and its ligand might contribute to B-CLL survival through the modulation of the Bcl-2/Bax ratio.
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PMID:CD6 ligation modulates the Bcl-2/Bax ratio and protects chronic lymphocytic leukemia B cells from apoptosis induced by anti-IgM. 910 2

The a beta peptide induces cell death in neurons grown in cell culture. Previous studies have shown that the mechanism of a beta-mediated cell death of central nervous system neurons appears to be via apoptosis. Apoptosis is an active process that involves both gene transcription and translation. Using semi-quantitative polymerase chain reaction, we have analyzed the levels of a variety of transcripts in primary neuronal cultures treated with a beta that are likely to play important roles in apoptosis. Following addition of 10 microM a beta 1-42 the immediate early response gene, c-fos, shows a rapid and sustained increase in transcript level while c-jun levels increase at a slower rate. Bcl-2 and its homologues, bcl-X and bax, also increase in amount with bcl-2 and bcl-X increasing more rapidly than bax. These data provide support indicating that a beta-mediated cell death in central nervous system neurons is an active process similar to that seen in apoptosis.
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PMID:Changes in gene transcription during a beta-mediated cell death. 911 17

Inactivation of p53-dependent apoptosis promotes oncogenic transformation, tumor development, and resistance to many cytotoxic anticancer agents. p53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis. To determine whether bax is required for p53-dependent apoptosis, the effects of bax deficiency were examined in primary fibroblasts expressing the E1A oncogene, a setting where apoptosis is dependent on endogenous p53. We demonstrate that bax can function as an effector of p53 in chemotherapy-induced apoptosis and contributes to a p53 pathway to suppress oncogenic transformation. Furthermore, we show that additional p53 effectors participate in these processes. These p53-controlled factors act synergistically with Bax to promote a full apoptotic response, and their action is suppressed by the Bcl-2 and E1B 19K oncoproteins. These studies demonstrate that Bax is a determinant of p53-dependent chemosensitivity and illustrate how p53 can promote apoptosis by coordinating the activities of multiple effectors.
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PMID:bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. 912 97

To understand the effects of ionizing radiation on thyroid cells, we investigated the role of p53 in mediating apoptosis and in DNA repair following in vivo and in vitro irradiation of thyroid cells. In vitro exposure of human thyroid cells to ionizing radiation of up to 5-8 Gy failed to induce apoptosis in primary cells. The same results were obtained when the thyroid gland was irradiated in the intact rat. To explore the mechanism of failure of the wild-type p53 in inducing apoptosis in thyroid cells, we investigated the expression of apoptosis-related genes, bax, bcl-2 and fas/APO-1 following irradiation or induction of temperature-sensitive p53. The expression of Bax, Bcl-2 and Fas/APO-1 in human primary cultured thyroid cells did not change after irradiation. To further confirm the results, we established a clonal cell line (tsFRO) in which a temperature sensitive p53 (Val138) expression vector was stably transfected to a thyroid carcinoma cell line lacking endogenous p53. Incubation of tsFRO cells at the permissive temperature for three days, however, did not induce apoptosis although G1 arrest was noted. Although enhanced expression of the bax mRNA level was observed, the expression of Bax, Bcl-2 and Fas/APO-1 protein did not change by shifting tsFRO cells to permissive temperature as well as irradiated primary cells. Furthermore, DNA end-jointing ability was examined by transfection of linearized luciferase plasmid into tsFRO cells. Increased luciferase activity occurred when the cells were cultured at the permissive temperature, indicating that the wild-type p53 enhances DNA end-jointing activity. Our results indicate that the wild-type p53 does not lead to apoptosis but facilitates DNA end-jointing in thyroid cells. These results may reflect specific responses in thyroid cells following irradiation.
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PMID:p53 induced by ionizing radiation mediates DNA end-jointing activity, but not apoptosis of thyroid cells. 912 41

Interleukin-10 (IL-10), a cytokine from mouse Th2 cells and macrophage that inhibits IL-2 and IFN-gamma production by Th1 cells, has been reported to stimulate growth and differentiation of B cells activated by CD40 or antigen receptor crosslinking. Our early observation revealed that IL-10 had B cell growth factor (BCGF) activity in human B cells preactivated with SAC or anti-Ig. The responsiveness of the preactivated B cells to IL-10 greatly increased when B cells were activated in the presence of IL-2, whereas IL-10 has no BCGF activity when added at the initiation of activation by SAC. To investigate the dual effects (proliferation and apoptosis) of IL-10 on B cells, the expression of a panel of bcl-2 protoncogene family members, bcl-2, bcl-x, mcl-1, and bax, was analyzed when B cells were activated by SAC. Bcl-xL protein was not expressed in the small resting B cells but was induced by SAC stimulation, reaching its peak at 48 hr. The addition of IL-2 further augmented the Bcl-xL expression with the same kinetics, whereas Bcl-2 and Mcl-1 were expressed by resting B cells and enhanced by SAC stimulation. However, the addition of IL-10 at the initiation of activation down-regulated Bcl-xL, Bcl-2, and Mcl-1 expression. At the same time, B cell proliferation was inhibited and apoptotic cell number increased, suggesting the growth arrest and/or apoptosis of B cells. The apoptosis of SAC-activated B cells by IL-10 was further confirmed by propidium iodide-staining and Annexin V-FITC-staining methods. In contrast, IL-10 failed to down-regulate the Bcl-xL and Bcl-2 expression but rather augmented the expression of Mcl-1 of B cells after preactivation for 48 hr with SAC and IL-2. Under this culture condition, B cells responded to IL-10 to proliferate and differentiate, while IL-2 and IL-10 had an additive or synergistic effect. Taken together, our data suggest that IL-10 acts on the induction stage of Bcl-xL expression and regulates the apoptosis and proliferation of SAC-activated B cells through their bcl-2 family gene expression.
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PMID:The apoptosis and proliferation of SAC-activated B cells by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 expression. 918 96

Bcl-2 over-expression has been shown to inhibit apoptosis induced by a variety of stimuli, whereas a predominance of Bax alpha to Bcl-2 accelerates apoptosis upon apoptotic stimuli. We sought to study the relevance of these apoptotic regulating gene products in leukaemia. In a panel of leukaemia and lymphoma cell lines (HL60, DoHH2, CEM C7, L1210 and S49), the Bax alpha-to-Bcl-2 ratio as assessed by Western-blot analysis correlated with sensitivity to dexamethasone treatment. In addition, in HAbax alpha-transfected CEM C7 clones, a similar correlation was found for dexamethasone and thapsigargin sensitivity. In bone-marrow aspirates from patients with childhood acute lymphoblastic or myelocytic leukaemia (ALL, n = 48; AML, n = 8), the Bcl-2 and Bax alpha levels were highly variable, but well within the range found in the Bax alpha transfectants and in the established cell lines. Bcl-2 levels were lower in T- than in B-lineage ALL, which could be ascribed to simultaneous inverse relation between Bcl-2 and WBC. By contrast, Bax alpha:Bcl-2 was independent of any presenting feature and was largely dependent on Bax alpha levels. Results suggest that Bax alpha:Bcl-2, rather than Bcl-2 alone is important for the survival of drug-induced apoptosis in leukemic cell lines and ALL.
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PMID:The Bax alpha:Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia. 918 97

In this study, we tested the hypothesis that insulin-like growth factor-1 (IGF-1) modulates apoptosis in human breast cancer cells, HBL100, induced by diverse chemotherapeutic drugs. IGF-1 increased cell survival of HBL100 cells treated with 5-fluorouracil (antimetabolite), methotrexate (antimetabolite), tamoxifen (antiestrogen/antiproliferative), or camptothecin (topoisomerase 1 inhibitor) and after serum withdrawal. Elevated cell survival was not due to an increase in cell proliferation by IGF-1, but rather to an inhibition of apoptosis. Evidence for death by apoptosis was supported by cellular morphology and DNA fragmentation. There were no changes observed in Bcl-2 protein or bax mRNA levels. Extracellular matrix (ECM) is known to influence the apoptotic response of cells; therefore, the antiapoptotic effect of IGF-1 on breast cancer cells was examined using different ECMs: laminin, collagen IV, or Matrigel. IGF-1 protected cells from apoptosis induced by methotrexate on all ECMs tested, providing the first evidence that IGF-1 protects against apoptosis in three-dimensional culture systems. These data provide the rationale to search for drugs that lower serum IGF-1 in an effort to improve the efficacy of chemotherapeutic drugs for the treatment of breast cancer.
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PMID:Insulin-like growth factor 1 (IGF-1) alters drug sensitivity of HBL100 human breast cancer cells by inhibition of apoptosis induced by diverse anticancer drugs. 920 78


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