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)

Our previous data have shown that isolated leukemic cells from progressive chronic lymphocytic leukemia (B-CLL) patients respond to growth stimulation in vitro and express high levels of p53, immunoreactive with the configuration-specific antibody PAb 240. We have now analyzed the in vitro survival of B-CLL cells in relation to Bcl-2, Bax alpha and p53 expression and compared this with the clinical progression of the disease. Leukemic cells from patients with progressive disease demonstrated higher in vitro survival, compared with non-progressive B-CLL and normal B cells. All cells were sensitive to treatment with a combination of glucocorticoid and cAMP. Bcl-2 protein levels were not related to clinical progression, as measured by flow cytometry. Competitive PCR showed that Bcl-2 mRNA was over-expressed in most of the B-CLL samples and that p53 mRNA expression was similar between B-CLL groups and normal values and thus not related to clinical progression. However, since Bax alpha expression was lower in progressive than in non-progressive patients, the Bcl-2/Bax alpha ratio at the mRNA level was significantly higher in the progressive group. Our data suggest that the Bcl-2/Bax alpha ratio is important for the regulation of B-CLL cell survival, that p53 over-expression in progressive B-CLL is the result of post-transcriptional modifications and that a directed PKA activation may potentiate the cytolytic effect of glucocorticoids in vivo.
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PMID:Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression. 860 78

The authors recently reported that CD2 ligation rescues B cells from antigen-induced apoptosis by upregulation of intracellular Bcl-2 levels. However, the characterization of the early signals involved in apoptosis rescue by CD2 ligation has not been well established. In this context, CD2 does not promote either phosphatidylinositol turnover or CA2+ mobilization in B cells. In this paper the authors show that CD2 interaction with its ligand CD48 also reduces the apoptosis induced by forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and, to a much lesser extent, the apoptosis induced by cholera toxin in murine B splenocytes. Using a cAMP detection system sensitive to the picomolar range, the authors demonstrate that CD2-CD48 interaction decreases the intracellular cAMP concentrations induced by forskolin but not by cholera toxin. In comparison with the CD2-CD48 interaction, CD40-CD40 ligand interaction completely inhibits the apoptosis induced by cAMP increases without affecting the intracellular cAMP levels promoted by forskolin or cholera toxin. These results indicate that CD2 can also control the apoptosis at the very early steps after receptor signalling, such as the adenylate cyclase activity. Given that heterotrimeric G-proteins can mediate the adenylate cyclase activity the authors suggest that CD2 signalling could act through these small proteins, which would explain the inability of CD2 signalling to rescue from the apoptosis induced by cholera toxin, a Gs-protein activator. Conversely, CD40 seems to control apoptosis further downstream of the cAMP-PKA pathway where the survival and apoptotic signals are confluent, which might therefore render it a more efficient system to block apoptosis.
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PMID:Decrease in cAMP levels promoted by CD48-CD2 interaction correlates with inhibition of apoptosis in B cells. 866 20

Activation of several different kinases characterizes the induction of apoptosis. Abelson virus transformed pre-B lymphocytes undergo apoptosis within 24 h of serum deprivation, PKA activation or gamma-irradiation, and the activity of two kinases of ca. 40 and 44 kDa is specifically induced during this apoptotic process. Bcl-2 expression prevents both apoptosis and the induction of these kinases. Immunologic and substrate similarities indicate that these kinases are related to the p38 family of MAP kinases. More mature cells of the B lymphocytic lineage, plasmacytomas, also exhibit induction of these kinases when apoptosis is induced by withdrawal of serum or IL-6. Treatment of the pre-B cells with ICE protease inhibitors when apoptotic stimuli are delivered prevents induction of the kinase activity, and partially inhibits apoptosis. These findings indicate that the induction of these 40 and 44 kDa p38 related kinases is a common feature of apoptosis in mouse B lymphocytic cells and may represent a step downstream of ICE proteases in the signal cascade that leads to programmed cell death.
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PMID:Activation of bcl-2 suppressible 40 and 44 kDa p38-like kinases during apoptosis of early and late B lymphocytic cell lines. 961 94

The Bcl-2 family protein BAD promotes apoptosis by binding through its BH3 domain to Bcl-x(L) and related cell death suppressors. When BAD is phosphorylated on either Ser(112) or Ser(136), it forms a complex with 14-3-3 in the cytosol and no longer interacts with Bcl-x(L) at the mitochondria. Here we show that phosphorylation of a distinct site Ser(155), which is at the center of the BAD BH3 domain, directly suppressed the pro-apoptotic function of BAD by eliminating its affinity for Bcl-x(L). Protein kinase A functioned as a BAD Ser(155) kinase both in vitro and in cells. BAD Ser(155) was found to be a major site of phosphorylation induced following stimulation by growth factors and prevented by protein kinase A inhibitors but not by inhibitors of the phosphatidylinositol 3-kinase/Akt pathway. Growth factors inhibited BAD-induced apoptosis in both a Ser(112)/Ser(136)- and a Ser(155)-dependent fashion. Thus, growth factors engage an anti-apoptotic signaling pathway that inactivates BAD by direct modification of its BH3 cell death effector domain.
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PMID:Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. 1083 73

Advances in molecular and cell biology have led to further understanding of the mechanisms of malignant growth and metastasis in human breast cancer cells. Initiation and progression of breast cancer results from mutations and the abnormal expression of many genes that control cellular proliferation, differentiation, invasion, metastasis and sensitivity to therapy (chemotherapy and radiation therapy). Inhibition of host immunity also plays a role in breast cancer progression. Many genes have been selected as targets for antisense therapy, including HER-2/neu, PKA, TGF-alpha, EGFR, TGF-beta, IGFIR, P12, MDM2, BRCA, Bcl-2, ER, VEGF, MDR, ferritin, transferrin receptor, IRE, C-fos, HSP27, C-myc, C-raf and metallothionein genes. The strategy behind antisense therapy is the development of specific therapeutic agents that aim to correct the mutations and abnormal expression of cellular genes in breast tumour cells by decreasing gene expression, inducing degradation of target mRNA and causing premature termination of transcription. Many in vitro and in vivo studies have investigated the therapeutic efficacy of oligonucleotides and antisense RNAs. These studies have demonstrated specific inhibition of tumour cell growth by antisense therapy and have shown synergistic inhibitory effects between antisense oligonucleotides or antisense RNA and conventional chemotherapeutic drugs used in the treatment of breast cancer. Antisense oligonucleotides have been modified to improve their ability to penetrate cells, bind to gene sequences and downregulate target gene function. Many delivery systems for antisense RNA and antisense oligonucleotides have been developed, including virus vectors (retrovirus, adenovirus and adeno-associate virus) and liposomes, to carry the antisense RNA or oligonucleotides through the cell membrane into the cytoplasm and nucleus of the tumour cells. However, in order to determine their feasibility antisense therapies need to be further investigated to determine their antitumour activity, pharmacokinetics and toxicity in breast cancer patients.
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PMID:Gene targets of antisense therapies in breast cancer. 1222 74

Evidence from live cell bioassays shows that the flat mucosa from patients with colon cancer exhibits resistance to bile salt-induced apoptosis. Three independent cell lines derived from the colonic epithelial cell line HCT-116 were selected for resistance to bile salt-induced apoptosis. These cell lines were developed as tissue culture models of apoptosis resistance. Selection was carried out for resistance to apoptosis induced by sodium deoxycholate (NaDOC), the bile salt found in highest concentrations in human fecal water. Cultures of HCT-116 cells were serially passaged in the presence of increasing concentrations of NaDOC. The resulting apoptosis resistant cells were able to grow at concentrations of NaDOC (0.5 mM) that cause apoptosis in a few hours in unselected HCT-116 cells. These cells were then analyzed for changes in gene expression. Observations from cDNA microarray, 2-D gel electrophoresis/MALDI-mass spectroscopy, and confocal microscopy of immunofluorescently stained preparations indicated underexpression or overexpression of numerous genes at either the protein or mRNA level. Genes that may play a role in apoptosis and early stage carcinogenesis have been identified as upregulated in these cell lines, including Grp78, Bcl-2, NF-kappaB(p50), NF-kappaB(p65), thioredoxin peroxidase (peroxiredoxin) 2, peroxiredoxin 4, maspin, guanylate cyclase activating protein-1, PKCzeta, EGFR, Ras family members, PKA, PI(4,5)K, TRAF2 and BIRC1 (IAP protein). Under-expressed mRNAs included BNIP3, caspase-6, caspase-3 and serine protease 11. NF-kappaB was constitutively activated in all three resistant cell lines, and was responsible, in part, for the observed apoptosis resistance, determined using antisense oligonucleotide strategies. Molecular and cellular analyses of these resistant cell lines has suggested potential mechanisms by which apoptosis resistance may develop in the colonic epithelium in response to high concentrations of hydrophobic bile acids that are associated with a Western-style diet. These analyses provide the rationale for the development of hypothesis-driven intermediate biomarkers to assess colon cancer risk on an individual basis.
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PMID:Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. 1250 30

Apoptosis and proliferation are intimately coupled. Some cell cycle regulators can influence both cell division and programmed cell death. The linkage of cell cycle and apoptosis has been recognized for c-Myc, p53, pRb, Ras, PKA, PKC, Bcl-2, NF-kappa B, CDK, cyclins and CKI. This review summarizes the different functions of the proteins presently known to control both apoptosis and cell cycle progression. These proteins can influence apoptosis or proliferation but different variables, including cell type, cellular environment and genetic background, make it difficult to predict the outcome of cell proliferation, cell cycle arrest or cell death. These important decisions of cell proliferation or cell death are likely to be controlled by more than one signal and are necessary to ensure a proper cellular response.
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PMID:Cell cycle and apoptosis. 1281 32

Signaling through the B cell antigen receptor (BCR) is a key determinant in the regulation of B cell physiology. Depending on additional factors, such as microenvironment and developmental stage, ligation of the BCR can trigger B lymphocyte activation, proliferation, or apoptosis. The regulatory mechanisms determining B cell apoptosis and survival are not completely known. Using the murine B lymphoma cell line WEHI-231 as a model system, we investigated the role of Bad phosphorylation, a pro-apoptotic member of the Bcl-2 family, in anti-IgM mediated apoptosis. For apoptotic analysis we focused in particular on the mitochondrial potential (deltapsi(m)) collapse which has been reported as a rate-limiting step in the BCR-induced cell death of immature B lymphocytes. Bad phosphorylation at serine 112, 136 and 155 was found in WEHI-231 cell control cultures and its hypophosphorylation on the three sites correlated with the appearance of apoptosis when cross-linking surface IgM. Furthermore, treatment of cells with specific PK inhibitors known to be involved in serine phosphorylation of Bad (LY294002 for PI3K and H-89 for PKA) mimiced or enhanced BCR-induced cell death. These results strongly suggest that regulation of Bad phosphorylation plays an active role in mediating anti-IgM-induced apoptosis of immature B cells.
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PMID:Changes in bad phosphorylation are correlated with BCR-induced apoptosis of WEHI-231 immature B cells. 1458 39

CGRP is a well-known neuropeptide that has various protective effects on cardiovascular system. Our previous studies have shown that CGRP inhibits vascular smooth muscle cell (VSMC) proliferation in vitro. The present study aimed to explore the role of the CGRP in neointimal formation after balloon injury in the rat aortic wall and the underlying mechanism. Gene transfer of CGRP was performed with the use of intramuscular electroporation in a balloon-injured rat aorta model. Apoptosis in VSMCs was determined by electrophoresis assessment of DNA fragmentation and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay. Overexpression of the CGRP gene significantly inhibited the neointimal formation after balloon injury compared with the mock transfer, as assessed by the intima-to-media ratio 14 days after balloon injury (29.2 +/- 3.7% vs. 52.7 +/- 5.4%; n = 9-12, P < 0.05). In addition, CGRP gene expression increased the number of apoptotic cells in the neointima in vivo 14 days after balloon injury. Similarly, the addition of bioactive CGRP and the nitric oxide donor induced similar apoptosis in cultured VSMCs. The antagonist of the CGRP(1) receptor and inhibitors of cAMP-PKA and nitric oxide blocked CGRP-mediated apoptosis. Furthermore, CGRP gene transfer increased inducible nitric oxide synthase and p53 but decreased PCNA and Bcl-2 protein levels in balloon-injured rat aorta. Our data demonstrated that CGRP potently inhibited neointimal thickening in the rat aorta, at least in part through its distinct effects on apoptosis and proliferation of VSMCs both in vivo and in vitro. Therefore, delivery of the CGRP gene may have therapeutic implications in limiting vascular restenosis.
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PMID:Intramuscular gene transfer of CGRP inhibits neointimal hyperplasia after balloon injury in the rat abdominal aorta. 1537 Dec 65

3,5,3'-triiodothyronine (T3) is essential for the growth and the regulation of metabolic functions, moreover, the growth-stimulatory effect of T3 has largely been demonstrated and the pathways via which T3 promotes cell growth have been recently investigated. Type 1 diabetes (T1D) is due to the destruction of beta-cells, which occurs even through apoptosis. Aim of our study was to analyze whether T3 could have an antiapoptotic effect on cultured beta-cells undergoing apoptosis. We have demonstrated that T3 promotes cell proliferation in islet beta-cell lines (rRINm5F and hCM) provoking an increment in cell number (up to 55%: rRINm5F and 45%: hCM), cell viability, and BrdU incorporation, and regulating the cell cycle-related molecules (cyc A, D1, E, and p27(kip1)). T3 inhibited the apoptotic process induced by streptozocin, S-Nitroso-N-Acetylpenicylamine (SNAP), and H2O2 via regulation of the pro- and anti-apoptotic factors Bcl-2, Bcl-XL, Bad, Bax, and Caspase 3. The T3 protective effect was PI-3 K-, but not MAPK- or PKA-mediated, involving pAktThr308. Thus, T3 could be considered a survival factor protecting islet beta-cells from apoptosis.
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PMID:3,5,3'-triiodothyronine (T3) is a survival factor for pancreatic beta-cells undergoing apoptosis. 1602 36


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