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)

This study shows the signaling pathway by which (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378) prevents tumor necrosis factor (TNF)-alpha-induced neuronal cell death. KR-31378 restored TNF-alpha-induced decreased cell viability of SK-N-SH. U87-MG cells (PTEN-null glioblastoma cell line) transfected with expression vectors for sense PTEN (phosphatase and tensin homolog deleted from chromosome 10) showed significantly decreased cell viability, which was restored by KR-31378. TNF-alpha-induced increased PTEN phosphorylation and decreased phosphorylation of Akt/cyclic AMP response element-binding protein (CREB) in SK-N-SH cells were concentration-dependently reversed by KR-31378, those of which were antagonized by iberiotoxin, a maxi-K channel blocker. TNF-alpha and apigenin, a casein kinase2 (CK2) inhibitor, showed decreased CK2 phosphorylation and increased PTEN phosphorylation, which were reversed by KR-31378. KR-31378 increased K(+) currents by activating the maxi-K channels in SK-N-SH cells, with suppression of TNF-alpha-induced increase in cytosolic Ca(2+) and elevation of suppressed mitochondrial membrane potential, all of which were antagonized by iberiotoxin. It is suggested that increase in cell viability by KR-31378 is ascribed to the maxi-K channel opening-coupled upregulation of CK2/Akt/CREB phosphorylation and downregulation of PTEN phosphorylation in association with increased Bcl-2 and decreased Bax levels.
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PMID:Anti-apoptotic action of (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378) by suppression of the phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and increased phosphorylation of casein kinase2/Akt/ cyclic AMP response element binding protein via maxi-K channel opening in neuronal cells. 1533 44

We have previously shown that low extracellular pH (pHe) promotes cell killing by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we examined whether amiloride, an inhibitor of the Na(+)/H(+) antiporter capable of lowering the intracellular pH (pHi), can potentiate TRAIL-induced apoptotic death. Human prostate adenocarcinoma DU-145 cells were treated with various concentrations of TRAIL (10-200 ng/ml) and/or amiloride (0.1-1 mM) for 4 h. Amiloride, which caused little or no cytotoxicity by itself, enhanced TRAIL-induced apoptosis. The TRAIL-mediated activation of caspase, and PARP (poly (ADP-ribose) polymerase) cleavage were both promoted by amiloride. Western blot analysis showed that combined treatment with TRAIL and amiloride did not change the levels of TRAIL receptors (death receptor (DR)4, DR5, and DcR2 (decoy recepter 2) or antiapoptotic proteins (FLICE-inhibitory protein (FLIP), inhibitor of apoptosis (IAP), and Bcl-2). However, unlike pHe, amiloride promoted the dephosphorylation of Akt. Interestingly, amiloride also induced the dephosphorylation of P13K (phosphatidylinositol 3-kinase) and PDK-1 (phosphoinositide-dependent kinase-1) kinases along with PTEN (phosphatase and tensin homolog deleted on chromosome 10) and PP1alpha phosphatases. In vitro kinase assays revealed that amiloride inhibited phosphorylation of kinases and phosphatases by competing with ATP. Taken together, the present studies suggest that amiloride enhances TRAIL-induced cytotoxicity by inhibiting phosphorylation of the PI3K-Akt pathway-associated kinases and phosphatases.
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PMID:Amiloride augments TRAIL-induced apoptotic death by inhibiting phosphorylation of kinases and phosphatases associated with the P13K-Akt pathway. 1555 24

Inhibition of nuclear factor (NF)-kappaB/Rel can sensitise many tumour cells to death-inducing stimuli, including chemotherapeutic agents, and there are data suggesting that disruption of NF-kappaB may be of therapeutic interest in melanoma. We found that rapamycin sensitised a human melanoma cell line, established from a patient, to the cytolytic effects of doxorubicin. Doxorubicin is a striking NF-kappaB/Rel-inducer, we therefore investigated if rapamycin interfered with the pathway of NF-kappaB/Rel activation, i.e. IkappaBalpha-phosphorylation, -degradation and NF-kappaB/Rel nuclear translocation, and found that the macrolide agent caused a block of IKK kinase activity that was responsible for a reduced nuclear translocation of transcription factors. Western blots for Bcl-2 and c-IAP1 showed increased levels of these anti-apoptotic proteins in cells incubated with doxorubicin, in accordance with NF-kappaB/Rel activation, while rapamycin clearly downmodulated these proteins, in line with its pro-apoptotic ability. The effect of the macrolide on NF-kappa B/Rel induction appeared to be independent of the block in the PI3k/Akt pathway, because it could not be reproduced by the phosphatidyl inositol 3 kinase (PI3k) inhibitor, wortmannin. Recently, the immunophilin, FKBP51, has been shown to be essential for the function of IKK kinase. We found high expression levels of FKBP51 in melanoma cells. Moreover, we confirmed the involvement of this immunophilin in the control of IKK activity. Indeed, IkappaBalpha could not be degraded when FKBP51 was downmodulated by short-interfering RNAs (siRNAs). These findings provide a possible mechanism for the downmodulation of NF-kappaB by rapamycin, since the macrolide agent specifically inhibits FKBP51 isomerase activity. In conclusion, our study demonstrates that rapamycin blocked NF-kappaB/Rel activation independently of PI3k/Akt inhibition suggesting that the macrolide agent could synergise with NF-kappaB-inducing anti-cancer drugs in PTEN-positive tumours.
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PMID:Rapamycin inhibits doxorubicin-induced NF-kappaB/Rel nuclear activity and enhances the apoptosis of melanoma cells. 1557 67

Prostate cancer is a major pathology in industrialized countries. Tumor growth usually results from increased cell proliferation, conjugated with an inhibition of programmed cell death (apoptosis). In this paper, after a short description of the apoptotic mechanisms and their methods of investigation, we review the present knowledge of the implication of different molecular actors in the regulation of apoptosis in prostate cancer cells. This review notably summarizes the present knowledge of the (de)regulation of the effects of androgens, p53, Bcl-2, Bcl-xL, Bax, Akt, PTEN, Par-4, clusterine, caspases and NF-kappaB in prostate adenocarcinoma cell lines and provides an appraisal of their therapeutic potential. A better knowledge of the apoptotic pathways in these cells could indeed allow the development of new selective and effective anti-cancer strategies.
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PMID:[Prostate carcinoma cell lines and apoptosis: a review]. 1565 57

The immune system is a complex entity designed to eliminate foreign intruding antigens and is influenced by and, in turn, influences the function of the reproductive system. Despite the widespread associations between immunology and reproductive medicine, the study of system interactions remains in its infancy. Many diverse facts are accumulating, and pieces of the puzzle are becoming available to provide a clearer picture. In this review article, we focus on the interactions between endocrine and immune systems in the human endometrium. Understanding the molecular pathways in endocrine-immune interactions in the human endometrium is crucial to understand events such as menstrual bleeding, tissue repair and regeneration, inflammation, angiogenesis, blastocyst implantation, and progression of pregnancy. These events require a balanced regulation of endometrial differentiation, proliferation, cell survival, leukocyte recruitment, apoptosis, and angiogenesis by sex steroids. In this review, we first outline the role of survival factors such as phosphoinositol 3-kinase/protein kinase B, PTEN, NFkappaB, and apoptotic molecules (Fas-FasL, Bcl-2). We then discuss their regulation by estrogen and progesterone in the endometrium. We present evidence for direct and/or indirect roles of steroid hormones on the expression of chemotactic cytokines (interleukin-8 and monocyte chemotactic protein-1) and on the survival versus apoptosis of resident endometrial cells (stromal, epithelial, and endothelial cells) and nonresident cells (leukocytes).
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PMID:Endocrine-immune interactions in human endometrium. 1573 Dec 99

Bcl-2/adenovirus E1B 19 kDa interacting protein 2 like-1 (BNIPL-1) is a novel human protein identified in our laboratory, which can interact with Bcl-2 and Cdc42GAP and induce apoptosis via the BNIP-2 and Cdc42GAP homology (BCH) domain. In the present study, we established the Hep3B-Tet-on stable cell line in which expression of BNIPL-1 can be induced by doxycycline. The cell proliferation activity assay showed that the overexpression of BNIPL-1 suppresses Hep3B cell growth in vitro. The differential expression profiles of 588 known genes from BNIPL-1-transfected Hep3B-Tet-on and vector control cells were determined using the Atlas human cDNA expression array. Fifteen genes were differentially expressed between these two cell lines, among which seven genes were up-regulated and eight genes were down-regulated by BINPL-1. Furthermore, the differential expression result was confirmed by semiquantitative RT-PCR. Among these differentially expressed genes, p16INK4, IL-12, TRAIL and the lymphotoxin beta gene involved in growth suppression or cell apoptosis were up-regulated, and PTEN involved in cell proliferation was down-regulated by BNIPL-1. These results suggest that BNIPL-1 might inhibit cell growth though cell cycle arrest and/or apoptotic cell death pathway(s).
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PMID:cDNA expression array analysis of gene expression in human hepatocarcinoma Hep3B cells induced by BNIPL-1. 1614 17

Cilostazol was developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3). The anti-platelet and vasodilator properties of cilostazol have been extensively characterized and considered to contribute to the variety of clinical effects such as intermittent claudication and recurrent stroke. In this review, the novel action mechanism (s) of cilostazol are overviewed with the focus on the action of cilostazol in in vitro and in vivo studies as a maxi-K channel opener targeting anti-apoptotic signaling pathways. Under treatment with cilostazol (10 mg/kg intravenously or 30 mg/kg orally), a significant reduction in cerebral infarct area was evident in rats subjected to ischemia/reperfusion. Increase in cyclic AMP and decrease in TNF-alpha levels were identified in the ipsilateral cortex under treatment with cilostazol accompanied by decreased Bax formation and cytochrome c release with increased Bcl-2 production in the penumbral area as well as in the in vitro human umbilical endothelial cells. Cilostazol suppressed TNF-alpha-induced decrease in viability of SK-N-SH (human neuroblastoma) cells and HCN-1A (human cortical neuron) cells in association with decrease in PTEN phosphorylation and increase in Akt/CREB phosphorylation with suppression of DNA fragmentation, all of which were antagonized by iberiotoxin, a maxi-K(+) channel blocker. Further, cilostazol prevented TNF-alpha-induced PTEN phosphorylation and apoptotic cell death via increased CK2 phosphorylation in the SK-N-SH cells. Cilostazol increased K(+) current in SK-N-SH cells by opening the maxi-K channels. Thus, it was suggested that the action of cilostazol to promote cell survival was ascribed to the maxi-K channel opening-coupled upregulation of CK2 phosphorylation and downregulation of PTEN phosphorylation with resultant increased phosphorylation of Akt and CREB. These in vitro data were confirmed in the in vivo results of rats subjected to focal transient ischemic damage.
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PMID:Cilostazol: therapeutic potential against focal cerebral ischemic damage. 1647 48

Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration. To address its underlying molecular pathogenesis, we generated and characterized loss-of-function mutants of Drosophila PTEN-induced putative kinase 1 (PINK1), a novel AR-JP-linked gene. Here, we show that PINK1 mutants exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Furthermore, transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl-2 demonstrated that mitochondrial dysfunction accounts for the degenerative changes in all phenotypes of PINK1 mutants. Notably, we also found that PINK1 mutants share marked phenotypic similarities with parkin mutants. Transgenic expression of Parkin markedly ameliorated all PINK1 loss-of-function phenotypes, but not vice versa, suggesting that Parkin functions downstream of PINK1. Taken together, our genetic evidence clearly establishes that Parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons.
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PMID:Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. 1681 Feb 37

The Ras/Raf/MEK/ERK and PI3K/PTEN/AKT signaling cascades play critical roles in the transmission of signals from growth factor receptors to regulate gene expression and prevent apoptosis. Components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf, PI3K, PTEN, Akt). Also, mutations occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. These pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of elevated activated Akt levels to phosphorylate and inactivate Raf-1. We have investigated the genetic structures and functional roles of these two signaling pathways in the malignant transformation and drug resistance of hematopoietic, breast and prostate cancer cells. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell-lineage-specific effects. Induced Raf expression can abrogate the cytokine dependence of certain hematopoietic cell lines (FDC-P1 and TF-1), a trait associated with tumorigenesis. In contrast, expression of activated PI3K or Akt does not abrogate the cytokine dependence of these hematopoietic cell lines, but does have positive effects on cell survival. However, activated PI3K and Akt can synergize with activated Raf to abrogate the cytokine dependence of another hematopoietic cell line (FL5.12) which is not transformed by activated Raf expression by itself. Activated Raf and Akt also confer a drug-resistant phenotype to these cells. Raf is more associated with proliferation and the prevention of apoptosis while Akt is more associated with the long-term clonogenicity. In breast cancer cells, activated Raf conferred resistance to the chemotherapeutic drugs doxorubicin and paclitaxel. Raf induced the expression of the drug pump Mdr-1 (a.k.a., Pgp) and the Bcl-2 anti-apoptotic protein. Raf did not appear to induce drug resistance by altering p53/p21Cip-1 expression, whose expression is often linked to regulation of cell cycle progression and drug resistance. Deregulation of the PI3K/PTEN/Akt pathway was associated with resistance to doxorubicin and 4-hydroxyl tamoxifen, a chemotherapeutic drug and estrogen receptor antagonist used in breast cancer therapy. In contrast to the drug-resistant breast cancer cells obtained after overexpression of activated Raf, cells expressing activated Akt displayed altered (decreased) levels of p53/p21Cip-1. Deregulated expression of the central phosphatase in the PI3K/PTEN/Akt pathway led to breast cancer drug resistance. Introduction of mutated forms of PTEN, which lacked lipid phosphatase activity, increased the resistance of the MCF-7 cells to doxorubicin, suggesting that these lipid phosphatase deficient PTEN mutants acted as dominant negative mutants to suppress wild-type PTEN activity. Finally, the PI3K/PTEN/Akt pathway appears to be more prominently involved in prostate cancer drug resistance than the Raf/MEK/ERK pathway. Some advanced prostate cancer cells express elevated levels of activated Akt which may suppress Raf activation. Introduction of activated forms of Akt increased the drug resistance of advanced prostate cancer cells. In contrast, introduction of activated forms of Raf did not increase the drug resistance of the prostate cancer cells. In contrast to the results observed in hematopoietic cells, Raf may normally promote differentiation in prostate cells which is suppressed in advanced prostate cancer due to increased expression of activated Akt arising from PTEN mutation. Thus in advanced prostate cancer it may be advantageous to induce Raf expression to promote differentiation, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK-induced proliferation. These signaling and anti-apoptotic pathways can have different effects on growth, prevention of apoptosis and induction of drug resistance in cells of various lineages which may be due to the expression of lineage-specific factors.
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PMID:Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. 1685 53

The phosphatidylinositol-3-OH kinase [PI(3)K] pathway is frequently activated in human cancers and represents a rational target for therapeutic intervention. We have previously shown that enforced expression of Akt, which is a downstream effector of PI(3)K, could promote tumorigenesis and drug resistance in the Emu-myc mouse lymphoma model, and that these tumors were particularly sensitive to inhibition of mammalian target of rapamycin (mTOR) with rapamycin when combined with conventional chemotherapy. We now show that reduced dosage of PTEN, a negative regulator of PI(3)K signaling, is sufficient to activate Akt, but has only a modest effect on lymphomagenesis in the same model. Nonetheless, loss of even one PTEN allele resulted in lymphomas that were resistant to conventional chemotherapy yet sensitive to rapamycin/chemotherapy combinations. These effects could be recapitulated by using RNA interference to suppress PTEN expression in lymphomas, which were previously established in the absence of PI(3)K lesions. Finally, the introduction of lesions that act downstream of mTOR (eIF4E) or disable apoptosis (Bcl-2 and loss of p53) into PTEN+/- lymphomas promoted resistance to rapamycin/chemotherapy combinations. Thus, whether activation of the PI(3)K pathway confers sensitivity or resistance to therapy depends on the therapy used as well as secondary genetic events. Understanding these genotype-response relationships in human tumors will be important for the effective use of rapamycin or other compounds targeting the PI(3)K pathway in the clinic.
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PMID:Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. 1688 64


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