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)

The Bcl-2 protein blocks programmed cell death (apoptosis) through an unknown mechanism. Previously we identified a Bcl-2 interacting protein BAG-1 that enhances the anti-apoptotic effects of Bcl-2. Like BAG-1, the serine/threonine protein kinase Raf-1 also can functionally cooperate with Bcl-2 in suppressing apoptosis. Here we show that Raf-1 and BAG-1 specifically interact in vitro and in yeast two-hybrid assays. Raf-1 and BAG-1 can also be coimmunoprecipitated from mammalian cells and from insect cells infected with recombinant baculoviruses encoding these proteins. Furthermore, bacterially-produced BAG-1 protein can increase the kinase activity of Raf-1 in vitro. BAG-1 also activates this mammalian kinase in yeast. These observations suggest that the Bcl-2 binding protein BAG-1 joins Ras and 14-3-3 proteins as potential activators of the kinase Raf-1.
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PMID:Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. 869 45

The role of the basal activity of the serine/threonine protein kinase, protein kinase C (PKC) in the regulation of anti-CD95-induced apoptosis in Jurkat T cells was investigated. The PKC-specific inhibitor GF 109203X and the proposed cPKC-specific inhibitor Go 6976, in a concentration-dependent manner, increased the percentage of cells undergoing apoptosis induced by anti-CD95 mAb as demonstrated by propidium iodide (PI) staining, TUNEL assay and DNA fragmentation by gel electrophoresis. Furthermore, Go 6976 and GF 109203X abrogated phorbol myristate acetate-induced inhibition of anti-CD95-induced apoptosis. To examine the molecular mechanism by which PKC modulates anti-CD95-induced apoptosis, the effects of Go 6976 on known effector and regulatory molecules of cell death were studied. Increased recruitment of cells undergoing apoptosis was associated with enhanced anti-CD95-induced proteolytic cleavage of the most receptor-proximal cysteine protease caspase-8, subsequent cleavage and activation of the machinery protease caspase-3, and cleavage of the caspase substrates DNA-dependent protein kinase catalytic subunit, poly-(ADP-ribose) polymerase and lamin B1. CD95 and FADD protein levels in Jurkat T cells were not altered by Go 6976 treatment. In addition, Go 6976 did not alter protein levels and subcellular distribution of the anti-apoptotic molecules Bcl-2 and Bcl-xL. These data suggest indirectly that basal PKC activity acts at an early stage in the anti-CD95-induced caspase pathway to attenuate subsequent activation of downstream effector molecules and associated apoptosis in Jurkat T cells.
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PMID:Inhibition of the protein kinase C pathway promotes anti-CD95-induced apoptosis in Jurkat T cells. 970 Oct 26

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in tumor cell lines, whereas normal cells appear to be protected from its cytotoxic effects. Therefore TRAIL holds promise as a potential therapeutic agent against cancer. To elucidate some of the critical factors that contribute to TRAIL resistance, we performed a genetic screen in the human colon carcinoma cell line SW480 by infecting this TRAIL-sensitive cell line with a human placental cDNA retroviral library and isolating TRAIL-resistant clones. Characterization of the resulting clones for inhibitors of TRAIL-induced death (ITIDs) led to the isolation of c-FLIP(S), Bax inhibitor 1, and Bcl-XL as candidate suppressors of TRAIL signaling. We have demonstrated that c-FLIP(S) and Bcl-XL are sufficient when overexpressed to convey resistance to TRAIL treatment in previously sensitive cell lines. Furthermore both c-FLIP(S) and Bcl-XL protected against overexpression of the TRAIL receptors DR4 and KILLER/DR5. When c-FLIP(S) and Bcl-XL were overexpressed together in SW480 and HCT 116, an additive inhibitory effect was observed after TRAIL treatment suggesting that these two molecules function in the same pathway in the cell lines tested. Furthermore, we have demonstrated for the first time that a proapoptotic member of the Bcl-2 family, Bax, is required for TRAIL-mediated apoptosis in HCT 116 cells. Surprisingly, we have found that the serine/threonine protein kinase Akt, which is an upstream regulator of both c-FLIP(S) and Bcl-XL, is not sufficient when overexpressed to protect against TRAIL in the cell lines tested. These results suggest a key role for c-FLIP(S), Bcl-XL, and Bax in determining tumor cell sensitivity to TRAIL.
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PMID:Identification of inhibitors of TRAIL-induced death (ITIDs) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach. 1148 1

Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin beta 1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged <50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P=0.001) and the presence of heregulin beta 1-expressing stromal cells (P=0.017). Neither Akt-1 nor pAkt was related with other factors. Tumour cells-derived heregulin beta 1 was found mainly in oestrogen receptor negative (P=0.026) and node negative (P=0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P=0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer.
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PMID:Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. 1187 May 34

Viruses have evolved different strategies to interfere with apoptotic pathways in order to halt cellular responses to infection. The herpes simplex virus 1 (HSV-1) Us3 open-reading frame encodes a serine/threonine protein kinase that participates in the inhibition of apoptosis induced by virus infection and other stress agents. Previous studies have shown that Us3 counteracts the virus-induced activation of caspase-3 by acting at a premitochondrial stage. Using stable transfectants that express Us3 under the control of constitutive or inducible promoters we demonstrate that apoptosis induced by treatment with anti-Fas antibody and sorbitol is blocked when Us3 is expressed at levels comparable to those achieved during virus infection. Expression of Us3 correlated with phosphorylation of Bad, a BH3-only proapoptotic Bcl-2 family member that is also a target for growth factor-induced cellular kinases. Bad was phosphorylated by Us3 in in vitro kination assays. These results point to a strategy for viral inhibition of apoptosis based on functional inactivation of a critical component of the cellular death machinery.
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PMID:The Us3 protein kinase of herpes simplex virus 1 blocks apoptosis and induces phosporylation of the Bcl-2 family member Bad. 1459 23

The expression and activation of serine/threonine protein kinase, Akt, in leiomyoma and in adjacent myometrium of human uteri was studied parallel with the changes of Bcl-2, Bax proteins, estrogen and progesterone receptors during menstrual cycle and early stage of the menopause. Abundant expression of Akt protein was detected in the studied tissues during menstrual cycle, the rate of increase was higher in leiomyoma than in corresponding myometrium. The expression of estrogen receptor alpha, progesterone receptor and of Bcl-2 protein changed parallel with that of Akt protein. The level of phosphorylated Akt (pAkt(473)) was seen only in leiomyoma samples from the growing period of tumors. At early stage of menopause levels of all studied proteins were lower than that in the menstrual cycle with the exception of Bax protein expression, which was high in leiomyoma. Our data suggest the involvement of phosphatidylinositol 3-kinase/Akt signaling in the pathomechanism of leiomyoma.
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PMID:Differential expression of Akt/protein kinase B, Bcl-2 and Bax proteins in human leiomyoma and myometrium. 1469 3

We found that the expression of mitochondrial apoptosis related genes (Bcl-2 associated protein X, BAX; apoptotic protease activating factor 1, Apaf-1; Caspase 9 and serine/threonine protein kinase, PKB) is elevated in Trichinella spiralis-infected muscles during encapsulation. Micro-dissection of the capsule and subsequent reverse transcription polymerase chain reaction (RT-PCR) confirmed that the expressions of these genes are restricted to the nurse cell. Immunocytochemistry revealed that pro-apoptosis factor (BAX, Apaf-1 and Caspase 9) are predominantly expressed in the basophilic cytoplasm (infected muscle cell origin) and anti-apoptosis factor (PKB) in the eosinophilic cytoplasm (satellite cell origin) of the nurse cell. Electron microscopy revealed that the pre-existing mitochondria in the muscle cells became swollen and disappeared immediately after newborn larva invasion, but new mitochondria of smaller size appeared in the cytoplasm. Nuclear fragmentation and condensation were observed in basophilic cytoplasm which is known to die. Together, the results suggest that the infected muscle cells transform but die through the process of apoptosis which is triggered by factors from the newly formed mitochondria. The anti-apoptosis factor may help the eosinophilic cytoplasm with its survival to ensure nurse cell function.
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PMID:Expression of apoptosis-related factors in muscles infected with Trichinella spiralis. 1507 81

Granulocytes are critical components of the innate immune system whose lifespan is limited by an intrinsic, constitutive, apoptotic pathway. However, the lifespan of these cells can be extended at an inflammatory locus through interaction with survival factors. Although a wide variety of factors can modulate granulocyte survival, they often utilize a common subset of intracellular signal transduction pathways. Over the last decade, evidence has accumulated that the PI3K (phosphatidylinositol 3-kinase) family of lipid kinases may be critical in regulating the ability of granulocytes to survive at inflammatory loci. Studies utilizing both pharmacological inhibitors of PI3K and isoform-specific knockout mice have demonstrated that this enzyme is needed for the anti-apoptotic effects of granulocyte survival factors. More recently, a serine/threonine protein kinase, termed protein kinase B (also known as c-akt), has been demonstrated to be important in modulating the prosurvival effects of PI3K activation. This can occur through modulation of the expression or phosphorylation of members of the Bcl-2 (B-cell lymphocytic-leukaemia proto-oncogene 2) family of apoptosis regulators. This review summarizes recent results that have implicated a role for PI3K in regulating granulocyte survival.
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PMID:Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase. 1515 66

Neurotoxicity associated with increased glutamate release results in cell death through both necrotic and apoptotic processes. In addition, tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, is a strong modulator of apoptosis in several cell types. The aims of this study were to test the hypothesis that TUDCA reduces the apoptotic threshold induced by glutamate in rat cortical neurons and examine potential transduction pathways involved in both apoptotic signaling and neuroprotection by TUDCA. The results demonstrated that exposure of cortical neurons to glutamate induced cytochrome c release and caspase activation, as well as morphologic changes of apoptosis. These events were associated with down-regulation of antiapoptotic members of the Bcl-2 family, Bcl-2 and Bcl-x(L), and dephosphorylation of the serine/threonine protein kinase Akt. Pretreatment with TUDCA significantly reduced glutamate-induced apoptosis of rat cortical neurons. In addition, TUDCA induced marked phosphorylation and translocation of Bad from mitochondria to the cytosol. Moreover, inhibition of the phosphatidylinositol 3-kinase (PI3K) survival pathway abrogated the protective effects of TUDCA, including phosphorylation and translocation of Bad. In conclusion, TUDCA appears to modulate glutamate-induced neuronal apoptosis, in part, by activating a PI3K-dependent Bad signaling pathway. These data suggest that TUDCA may be beneficial in treating neurodegenerative disorders in which increased glutamate levels contribute to the pathogenesis of the disease.
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PMID:The bile acid tauroursodeoxycholic acid modulates phosphorylation and translocation of bad via phosphatidylinositol 3-kinase in glutamate-induced apoptosis of rat cortical neurons. 1519 Jan 25

Akt, also known as protein kinase B, is a serine/threonine protein kinase with antiapoptotic activities; also, it is a downstream target of phosphatidylinositol 3-kinase. Here we show that Akt1/Akt2 play a critical role in osteoclast differentiation but not cell survival and that mammalian target of rapamycin (mTOR) and Bim, a pro-apoptotic Bcl-2 family member, are required for cell survival in isolated osteoclast precursors. To investigate the function of Akt1, Akt2, mTOR, and Bim, we employed a retroviral system for delivery of small interfering RNA into cells. Loss of Akt1 and/or Akt2 protein inhibited osteoclast differentiation due to down-regulation of IkappaB-kinase (IKK) alpha/beta activity, phosphorylation of IkappaB-alpha, nuclear translocation of nuclear factor-kappaB (NFkappaB) p50, and NFkappaB p50 DNA-binding activity. Surprisingly, deletion of Akt1 and/or Akt2 protein did not stimulate cleaved caspase-3 activity and failed to promote apoptosis. Conversely, loss of mTOR protein induced apoptosis due to up-regulation of cleaved caspase-3 activity. In addition, we found that mTOR is downstream of phosphatidylinositol 3-kinase (but not Akt) and that macrophage colony-stimulating factor regulates Bim expression through mTOR activation for cell survival. These results demonstrate that Akt1/Akt2 are key elements in osteoclast differentiation and that the macrophage colony-stimulating factor stimulation of mTOR leading to Bim inhibition is essential for cell survival in isolated osteoclast precursors.
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PMID:Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. 1554 69


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