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

Here we show that introduction of human bcl-2 gene into E1A+c-Ha-ras-transformed rat embryo fibroblasts, which are highly susceptible to proapoptotic stimuli and fail to be arrested at the G(1)/S boundary following genotoxic stresses, results not only in inhibition of apoptosis, but also in restoration of the G(1)/S arrest. Overexpression of Bcl-2 did not affect proliferation rate and saturation density of E1A+c-Ha-ras transformants. Genotoxic stresses caused prolong G(1)/S arrest in Bcl-2-overexpressing transformants. Remarkably, levels and activities of Cdk2, cyclins E/A, cyclin E-Cdk2 and cyclin A-Cdk2 were unchanged during G(1)/S arrest. Introduction of Bcl-2 into E1A+c-Ha-ras-transformants resulted in accumulation of p21/Waf-1 without inhibiting cyclin-Cdk complexes. In both parental and Bcl-2-overexpressing cells, p21/Waf-1 was coimmunoprecipitated with ERK 1,2 and JNK 1,2, whereas p38 was found in complexes with p21/Waf-1 only in Bcl-2-overexpressing transformants. JNK 1,2 and p38 but not ERK 1,2 were detected in complexes with the exogenous Bcl-2. However, Bcl-2 did not affect phosphorylation of ERK 1,2, JNK 1,2 and p38. G(1)/S arrest induced by adriamycin and serum withdrawal (but not by IR) was accompanied by release of active forms of p38 from complexes with Bcl-2. We suggest that Bcl-2 restores stress-induced G(1)/S arrest without inhibiting cyclin-Cdk2 complexes and MAPK pathways.
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PMID:Restoration of G1/S arrest in E1A+c-Ha-ras-transformed cells by Bcl-2 overexpression. 1549 6

Cisplatin is one of the most potent anticancer agents, displaying significant clinical activity against a variety of solid tumors. For more than two decades, the most effective systemic chemotherapy for non-small cell lung cancer (NSCLC), the leading cause of cancer morbidity and mortality among men and women in the western world, was cisplatin-based combination treatment. Unfortunately, the outcome of cisplatin therapy on NSCLC seems to have reached a plateau. Therefore, the biological mechanisms of cisplatin action need to be understood in order to overcome the treatment plateau on NSCLC. Moreover, the development of resistance is a hurdle in the use of this drug. The molecular mechanisms that underlie this chemoresistance are largely unknown. Possible mechanisms of acquired resistance to cisplatin include reduced intracellular accumulation of cisplatin, enhanced drug inactivation by metallothionine and glutathione, increased repair activity of DNA damage, and altered expression of oncogenes and regulatory proteins. In addition, it is generally accepted that cytotoxicity of cisplatin is mediated through induction of apoptosis and arrest of cell cycle resulting from its interaction with DNA, such as the formation of cisplatin-DNA adducts, which activates multiple signaling pathways, including those involving p53, Bcl-2 family, caspases, cyclins, CDKs, pRb, PKC, MAPK and PI3K/Akt. Increased expression of anti-apoptotic genes and mutations in the intrinsic apoptotic pathway may contribute to the inability of cells to detect DNA damage or to induce apoptosis. Towards an understanding of the molecular basis of the cellular response to cisplatin-based chemotherapy in NSCLC, in this review we provide some insights into the pathways involved in cisplatin damage from entering the cells to execution of apoptosis or survival of NSCLC cells. We believe that as more and more molecular mechanisms of response to cisplatin-based therapy are unraveled, this knowledge should provide a basis for further studies to improve our understanding of molecular events associated with lung NSCLC as well as to devise novel and effective therapeutic approaches to overcome the treatment plateau or reverse drug resistance in this disease.
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PMID:Molecular basis of cellular response to cisplatin chemotherapy in non-small cell lung cancer (Review). 1549 78

Interactions between the Chk1 inhibitor UCN-01 and the farnesyltransferase inhibitor L744832 were examined in human leukemia cells. Combined exposure of U937 cells to subtoxic concentrations of UCN-01 and L744832 resulted in a dramatic increase in mitochondrial dysfunction, apoptosis, and loss of clonogenicity. Similar interactions were noted in other leukemia cells (HL-60, Raji, Jurkat) and primary acute myeloid leukemia (AML) blasts. Coadministration of L744832 blocked UCN-01-mediated phosphorylation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), leading to down-regulation of phospho-cyclic adenosine monophosphate responsive element-binding protein (phospho-CREB) and -p90(RSK) and activation of p34(cdc2) and stress-activated protein kinase/ERK kinase/c-Jun N-terminal kinase (SEK/JNK). Combined treatment also resulted in pronounced reductions in levels of phospho-Akt, -glycogen synthase kinase-3 (-GSK-3), -p70(S6K), -mammalian target of rapamycin (-mTOR), -forkhead transcription factor (-FKHR), -caspase-9, and -Bad. Ectopic expression of Bcl-2 or Bcl-xL but not dominant-negative caspase-8 blocked UCN-01/L744832-mediated mitochondrial dysfunction and apoptosis but did not prevent activation of p34(cdc2) and JNK or inactivation of MEK/ERK and Akt. Enforced expression of myristoylated Akt but not constitutively active MEK significantly attenuated UCN-01/L744832-induced apoptosis. However, dual transfection with Akt and MEK resulted in further protection from UCN-01/L744832-mediated lethality. Finally, down-regulation of JNK1 by siRNA significantly reduced the lethality of the UCN-01/L744832 regimen. Together, these findings suggest that farnesyltransferase inhibitors interrupt the cytoprotective Akt and MAPK pathways while reciprocally activating SAPK/JNK in leukemia cells exposed to UCN-01 and, in so doing, dramatically increase mitochondria-dependent apoptosis.
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PMID:Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. 1549 23

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

The Bcl-2 family proapoptotic protein, Bax, redistributes to the mitochondrion in response to varied stimuli, triggering loss of mitochondrial integrity and apoptosis. Suppression of MAPK kinase (MEK1) by the reagent UO126 in activated T cells maintained in the cytokine IL-2 disrupts cytoplasmic localization of Bax and cell survival. UO126 triggers mitochondrial translocation of ectopically expressed Bax-GFP, and both UO126 and dominant negative MEK-1 (DN-MEK1) trigger increased apoptosis in Bax-GFP-expressing T cell lines. Because inhibition of PI3K or its target Akt also triggers mitochondrial translocation of Bax in T cells and apoptosis in Bax-transfected cell lines, we generated Bax deletion mutants to identify the region(s) that confers sensitivity to regulation by MEK1 and Akt. A deletion mutant (Bax(1-171)) without the C terminus mitochondrial targeting sequence or an Akt target site (Ser(184)) localizes to the cytoplasm and triggers low level apoptosis that is enhanced by DN-Akt or DN-MEK1. A construct that lacks the first 29 aa (Bax-delta29) largely localizes to mitochondria, is highly apoptogenic, and is not inhibited by Akt or MEK1. Furthermore, Bax-delta29 overcomes IL-2-dependent survival in a T cell line, whereas Bax triggers comparatively low levels of apoptosis in these cells. Cytoplasmic localization and regulation by MEK1 and Akt are restored in a mutant deleted of the first 13 aa (Bax-delta13). Taken together, our results identify a region in the Bax N terminus that determines cellular localization regulated by MEK- and Akt-dependent signaling in T cells.
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PMID:The Bax N terminus is required for negative regulation by the mitogen-activated protein kinase kinase and Akt signaling pathways in T cells. 1552 59

Bcl-xL and Bcl-2 are phosphorylated in response to microtubule inhibitors, but the kinase(s) responsible and the functional significance have remained unclear. In this study, we investigated the characteristics of Bcl-xL and Bcl-2 phosphorylation in KB-3 carcinoma cells treated with vinblastine. In both asynchronous and synchronous cell cultures, Bcl-xL and Bcl-2 underwent a well-defined and coordinated cycle of phosphorylation and dephosphorylation, with a lengthy period of phosphorylation preceding apoptosis induction, and with dephosphorylation closely correlated with initiation of apoptosis. Internally, validated inhibitors of JNK, ERK, p38(MAPK), or CDK1 failed to inhibit vinblastine-induced phosphorylation of Bcl-xL or Bcl-2. In vitro, Bcl-xL and Bcl-2 were poor substrates relative to c-Jun and ATF2 for active recombinant JNK1. Both Bcl-xL and Bcl-2 were localized primarily to the mitochondrial fraction in both control and vinblastine-treated cells, indicating that phosphorylation did not promote subcellular redistribution. Bcl-xL kinase activity was demonstrated in mitochondrial extracts from vinblastine-treated, but not control, cells. These findings suggest that phosphorylation of these key antiapoptotic proteins may be catalysed by a novel or unsuspected kinase that is activated or induced in response to microtubule damage. Furthermore, the same kinase and phosphatase system may be operating in tandem on both proteins, and phosphorylation appears to maintain their antiapoptotic function, whereas dephosphorylation may trigger apoptosis. These results provide evidence for a novel signaling pathway connecting microtubule damage to apoptosis induction, and help to clarify some of the controversy concerning the role of Bcl-2 phosphorylation in microtubule inhibitor-induced apoptosis.
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PMID:Characterization of vinblastine-induced Bcl-xL and Bcl-2 phosphorylation: evidence for a novel protein kinase and a coordinated phosphorylation/dephosphorylation cycle associated with apoptosis induction. 1553 23

Fas-mediated apoptosis has been proposed to play an important role in the pathogenesis of Hashimoto's thyroiditis. Normal thyroid cells are resistant to Fas-mediated apoptosis in vitro but can be sensitized by the unique combination of interferon-gamma and IL-1beta cytokines. We sought to examine the mechanism of this sensitization and apoptosis signaling in primary human thyroid cells. Without the addition of cytokines, agonist anti-Fas antibody treatment of the thyroid cells resulted in the cleavage of proximal caspases, but this did not lead to the activation of caspase 7 and caspase 3. Apoptosis associated with the cleavage of caspases 7, 3, and Bid, and the activation of mitochondria in response to anti-Fas antibody occurred only after cytokine pretreatment. Cell surface expression of Fas, the cytoplasmic concentrations of procaspases 7, 8, and 10, and the proapoptotic molecule Bid were markedly enhanced by the presence of the cytokines. In contrast, P44/p42 MAPK (Erk) appeared to provide protection from Fas-mediated apoptosis because an MAPK kinase inhibitor (U0126) sensitized thyroid cells to anti-Fas antibody. In conclusion, Fas signaling is blocked in normal thyroid cells at a point after the activation of proximal caspases. Interferon-gamma/IL-1beta pretreatment sensitizes human thyroid cells to Fas-mediated apoptosis in a complex manner that overcomes this blockade through increased expression of cell surface Fas receptor, increases in proapoptotic molecules that result in mitochondrial activation, and late caspase cleavage. This process involves Bcl-2 family proteins and appears to be compatible with type II apoptosis regulation.
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PMID:Induction and regulation of Fas-mediated apoptosis in human thyroid epithelial cells. 1556 45

Stromal cell-derived factor-1 (SDF-1/CXCL12) enhances the survival of hematopoietic stem and progenitor cells in synergy with other cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), steel factor, and thrombopoietin (TPO), and both the PI3K/Akt and MAPK pathways have been linked to this survival. To further evaluate intracellular signaling involved in SDF-1/CXCL12 survival effects, we investigated modulation of downstream signaling molecules. The synergistic survival enhancement of SDF-1/CXCL12 plus other cytokines were directly linked to enhanced phosphorylation of p70/85S6K and cAMP responsive element binding protein (CREB), as well as enhanced induction of the Bcl-2 family member Mcl-1. Most prominently, c-Fos, a component of AP1 transcription factor, was synergistically induced by SDF-1/CXCL12 plus other cytokines. These results suggest that SDF-1/CXCL12 enhanced cell survival in synergy with other cytokines involves activation of CREB and induction of Mcl-1 and c-Fos.
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PMID:Enhancement of cell survival by stromal cell-derived factor-1/CXCL12 involves activation of CREB and induction of Mcl-1 and c-Fos in factor-dependent human cell line MO7e. 1558 13

Cell death by apoptosis is important in immune cell homeostasis and in the defense against infectious microorganisms. The physiological event of uptake and intracellular destruction of bacteria is a powerful apoptotic stimulus to macrophages and neutrophil granulocytes. In this study, we provide a molecular analysis of phagocytosis-induced apoptosis. Apoptosis was blocked by Bcl-2 in a mouse macrophage cell line and in primary mouse macrophages. Analysis of the upstream mechanisms revealed that apoptosis was triggered by the Bcl-2 homology domain 3-only protein Bim/Bod. Contact with bacteria or bacterial components induced a strong increase in Bim-expression through TLR and MyD88. Inhibition of the MAPK p38 and JNK reduced both up-regulation of Bim and apoptosis. Phosphorylation of Bim was further observed in mouse macrophages, which appeared to be the result of TLR-dependent phosphatase inhibition. Although TLR-induced Bim was, unlike Bim in resting cells, not bound to the microtubuli cytoskeleton, the up-regulation of Bim was not sufficient to cause apoptosis. A second signal was required that was generated in the process of phagocytosis. Phagocytosis-induced apoptosis was strongly reduced in Bim(-/-) macrophages. These data provide the molecular context of a form of apoptosis that may serve to dispose of terminally differentiated phagocytes.
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PMID:Phagocytosis-induced apoptosis in macrophages is mediated by up-regulation and activation of the Bcl-2 homology domain 3-only protein Bim. 1563 85

Bcl-2-associated death protein (Bad), a member of the Bcl family, directs astrocytes in primary cultures to enter or resist apoptosis during ischemia in vitro. Under ischemia, Bad was the only Bcl family member whose expression was upregulated significantly during the early stages of an ischemic insult. Increased endogenous Bad was translocated from the cytoplasm to mitochondria to induce apoptosis in astrocytes. Concurrently, ischemia also induced Bad phosphorylation specifically on Ser112 to promote survival. This site-specific phosphorylation of Bad was mediated by an early activation of the mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) intracellular signaling pathway. This study demonstrates that ischemia-induced Bad plays a dual role in determining whether astrocytes enter or resist apoptosis after an ischemic insult.
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PMID:Inactivation of bad by site-specific phosphorylation: the checkpoint for ischemic astrocytes to initiate or resist apoptosis. 1567 42


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