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)

Bax, a death-promoting member of the Bcl-2 family of proteins, triggered cell death when expressed in plants from a tobacco mosaic virus vector. Analysis of Bax deletion mutants demonstrated a requirement for the BH1 and BH3 domains in promoting rapid cell death, whereas deletion of the carboxyl-terminal transmembrane domain completely abolished the lethality of Bax in plants. The phenotype of cell death induced by Bax closely resembled the hypersensitive response induced by wild-type tobacco mosaic virus in tobacco plants carrying the N gene. The cell death-promoting function of Bax in plants correlated with accumulation of the defense-related protein PR1, suggesting Bax activated an endogenous cell-death program in plants. In support of this view, both N gene- and Bax-mediated cell death was blocked by okadaic acid, an inhibitor of protein phosphatase activity. The ability of Bax to induce cell death and a defense reaction in plants suggests that some features of animal and plant cell death processes may be shared.
 ...
PMID:Bax-induced cell death in tobacco is similar to the hypersensitive response. 1039 29

Bcl-2 inhibits apoptosis induced by a variety of stimuli, including chemotherapy drugs and glucocorticoids. It is generally accepted that Bcl-2 exerts its antiapoptotic effects mainly by dimerizing with proapoptotic members of the Bcl-2 family such as Bax and Bad. However, the mechanism of the antiapoptotic effects is unclear. Paclitaxel and other drugs that disturb microtubule dynamics kill cells in a Fas/Fas ligand (FasL)-dependent manner; antibody to FasL inhibits paclitaxel-induced apoptosis. We have found that Bcl-2 overexpression leads to the prevention of chemotherapy (paclitaxel)-induced expression of FasL and blocks paclitaxel-induced apoptosis. The mechanism of this effect is that Bcl-2 prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes, a transcription factor activated by microtubule damage) by binding and sequestering calcineurin, a calcium-dependent phosphatase that must dephosphorylate NFAT to move to the nucleus. Without NFAT nuclear translocation, the FasL gene is not transcribed. Thus, it appears that paclitaxel and other drugs that disturb microtubule function kill cells at least in part through the induction of FasL. Furthermore, Bcl-2 antagonizes drug-induced apoptosis by inhibiting calcineurin activation, blocking NFAT nuclear translocation, and preventing FasL expression. The effects of Bcl-2 can be overcome, at least partially, through phosphorylation of Bcl-2. Phosphorylated Bcl-2 cannot bind calcineurin, and NFAT activation, FasL expression, and apoptosis can occur after Bcl-2 phosphorylation.
 ...
PMID:Bcl-2-mediated drug resistance: inhibition of apoptosis by blocking nuclear factor of activated T lymphocytes (NFAT)-induced Fas ligand transcription. 1043 88

Calcineurin is a Ca(2+)/calmodulin-dependent protein phosphatase that is abundantly expressed in several specific areas of the brain, which are exceptionally vulnerable to stroke, epilepsy, and neurodegenerative diseases. In this study, we assessed the effects of high level activity of calcineurin on neuronal cells. Virus-mediated high level constitutive activity of calcineurin rendered neuronal cells susceptible to apoptosis induced by serum reduction or by a brief exposure to calcium ionophore. Adenovirus-mediated, high level forced activity of calcineurin induced cytochrome c/caspase-3-dependent apoptosis in neurons. Preincubation with the calcineurin inhibitors cyclosporin A and FK506 reduced susceptibility to apoptosis. High level constitutive expression of Bcl-2 or CrmA or incubation with a specific caspase-3 inhibitor inhibited the calcineurin-induced apoptosis. These data indicate that high level constitutive activity of calcineurin predisposes neuronal cells to cytochrome c/caspase-3 dependent apoptosis even under sublethal conditions.
 ...
PMID:High level calcineurin activity predisposes neuronal cells to apoptosis. 1056 26

The protein phosphatase (PP) inhibitors nodularin and microcystin-LR induced apoptosis with unprecedented rapidity, more than 50% of primary hepatocytes showing extensive surface budding and shrinkage of cytoplasm and nucleoplasm within 2 min. The apoptosis was retarded by the general caspase inhibitor Z-VAD.fmk. To circumvent the inefficient uptake of microcystin and nodularin into nonhepatocytes, toxins were microinjected into 293 cells, Swiss 3T3 fibroblasts, promyelocytic IPC-81 cells, and NRK cells. All cells started to undergo budding typical of apoptosis within 0.5 - 3 min after injection. This was accompanied by cytoplasmic and nuclear shrinkage and externalization of phosphatidylserine. Overexpression of Bcl-2 did not delay apoptosis. Apoptosis induction was slower and Z-VAD.fmk independent in caspase-3 deficient MCF-7 cells. MCF-7 cells stably transfected with caspase-3 showed a more rapid and Z-VAD.fmk dependent apoptotic response to nodularin. Rapid apoptosis induction required inhibition of both PP1 and PP2A, and the apoptosis was preceded by increased phosphorylation of several proteins, including myosin light chain. The protein phosphorylation occurred even in the presence of apoptosis-blocking concentrations of Z-VAD.fmk, indicating that it occurred upstream of caspase activation. It is suggested that phosphatase-inhibiting toxins can induce caspase-3 dependent apoptosis in an ultrarapid manner by altering protein phosphorylation.
 ...
PMID:Ultrarapid caspase-3 dependent apoptosis induction by serine/threonine phosphatase inhibitors. 1057 79

Two p53-null T lymphoma cell lines proved to be highly sensitive to inhibition of gene expression. With either actinomycin D or cycloheximide, apoptosis commenced within 2 h, as indicated by loss of membrane integrity, degradation of certain proteins (including the phosphatase calcineurin) and DNA fragmentation. These effects were ablated by co-expression of Bcl-2 or co-incubation with the caspase inhibitor Z-VAD-fmk. These results suggest that the apoptotic machinery is in place in these cells but held in check by an unknown labile protein, which probably acts upstream of Bcl-2. Although cycloheximide can activate the JNK or p38 MAP kinases in some cells, neither was implicated here. However, disruption of phosphoinositide 3-kinase signaling may be involved, because the cells were also sensitive to wortmannin. The high sensitivity of the p53-null lymphoma cells to inhibitors of gene expression suggests that such inhibitors might prove useful in the cytotoxic therapy of certain tumors.
 ...
PMID:Interference with gene expression induces rapid apoptosis in p53-null T lymphoma cells. 1063 38

It is well known that human leukemia cells, such as HL-60 and U937 are sensitive to antitumor drugs, but human normal lung fibroblasts, such as WI-38 cells are resistant to the drugs. However, the mechanisms of the different responses to apoptosis in these cell lines remain unclear. We report here that an increase of Fas and Fas ligand (FasL) expression was required for antitumor drug-induced apoptosis in WI-38 and baby hamster kidney (BHK) cells, but not in HL-60 cells. Then, we used BHK cells transfected with the bcl-2 gene to investigate the involvement of complex formation of Bcl-2 and calcineurin. Calcineurin was imported to the nucleus in response to the drug treatment. Overexpression of Bcl-2 and cyclosporin A treatment inhibited the nuclear import and FasL expression, and as a result, both inhibited apoptosis. Although a caspase inhibitor, z-Asp-CH2-DCB, suppressed the drug-induced apoptosis, it failed to inhibit the drug-induced expression of Fas and FasL. These findings suggest that initially the Fas / FasL system is activated by calcineurin-dependent transcription followed by activation of the downstream caspase cascade resulting in antitumor drug-induced apoptosis in BHK cells, but not in HL-60 cells. Furthermore, Bcl-2 inhibits the nuclear import of calcineurin and suppresses calcineurin-mediated FasL expression during antitumor drug-induced apoptosis.
 ...
PMID:Bcl-2 inhibits calcineurin-mediated Fas ligand expression in antitumor drug-treated baby hamster kidney cells. 1092 Feb 78

Apoptosis of cardiac myocytes is one of the causes of heart failure. Here we examine the mechanism by which the activation of beta-adrenergic receptor induces cardiomyocyte apoptosis. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling and DNA ladder analyses revealed that isoproterenol (Iso) induced the apoptosis of cardiac myocytes of neonatal rats through an increase in intracellular Ca(2+) levels. The Iso-induced cardiomyocyte apoptosis was strongly inhibited by the L-type Ca(2+) channel antagonist nifedipine and by the calcineurin inhibitors cyclosporin A and FK506. Iso reduced the phosphorylation levels of the proapoptotic Bcl-2 family protein Bad and induced cytochrome c release from mitochondria to the cytosol through calcineurin activation. Infusion of Iso increased calcineurin activity by approximately 3-fold in the hearts of wild-type mice but not in the hearts of transgenic mice that overexpress dominant negative mutants of calcineurin. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling analysis revealed that infusion of Iso induced apoptosis of cardiac myocytes and that the number of apoptotic cardiomyocytes was significantly less in the hearts of the transgenic mice compared with the wild-type mice. These results suggest that calcineurin plays a critical role in Iso-induced apoptosis of cardiac myocytes, possibly through dephosphorylating Bad.
 ...
PMID:beta-Adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes. 1093 27

Bcl-2 is a gene with clear anti-apoptotic properties in neurodegenerative conditions. One of the earliest hallmarks of degeneration in neuronal cell cultures is the loss of neurite morphology. Therefore the effect of Bcl-2 on neuronal morphology and microtubule stability was studied in nerve growth factor differentiated PC12 cells. Microtubule dynamics were modulated using the microtubule stabilizer taxol and the microtubule destabilizer, okadaic acid, a protein phosphatase inhibitor. It was shown that Bcl-2 protects against both taxol- and okadaic acid induced neurite retraction. Bcl-2 overexpression also significantly reduced the increased ratio of acetylated tubulin over total tubulin induced by taxol treatment. Interestingly, Bcl-2 attenuates the decrease of the same ratio after exposure to okadaic acid, suggesting that Bcl-2 is able to normalize the level of acetylated tubulin. In addition, cell death and nuclear fragmentation, induced by okadaic acid, were reduced in Bcl-2 overexpressing cells. This protection is either downstream or independent of tau phosphorylation as quantitative immunocytochemistry with AT8 showed that Bcl-2 did not modify the level of tau phosphorylation. The data suggest that the protective effect of Bcl-2 on the neuronal cytoskeleton is probably linked to changes in the post-translational modification of tubulin.
 ...
PMID:Bcl-2 protects against apoptosis-related microtubule alterations in neuronal cells. 1122 90

Interleukin (IL)-3-induced Bcl2 phosphorylation at Ser(70) may be required for its full and potent antiapoptotic activity. However, in the absence of IL-3, increased expression of Bcl2 can also prolong cell survival. To determine how Bcl2 may be functionally phosphorylated following IL-3 withdrawal, a stress-activated Bcl2 kinase (SAK) was sought. Results indicate that anisomycin, a potent activator of the stress kinase JNK/SAPK, can induce Bcl2 phosphorylation at Ser(70) and that JNK1 can be latently activated following IL-3 withdrawal to mediate Bcl2 phosphorylation. JNK1 directly phosphorylates Bcl2 in vitro, co-localizes with Bcl2, and collaborates with Bcl-2 to mediate prolonged cell survival in the absence of IL-3 or following various stress applications. Dominant-negative (DN)-JNK1 can block both anisomycin and latent IL-3 withdrawal-induced Bcl2 phosphorylation (>90%) and potently enhances cell death. Furthermore, low dose okadaic acid (OA), a potent protein phosphatase 1 and 2A inhibitor, can activate the mitogen-activated protein kinases JNK1 and ERK1/2, but not p38 kinase, to induce Bcl2 phosphorylation and prolong cell survival in factor-deprived cells. Since PD98059, a specific MEK inhibitor, can only partially inhibit OA-induced Bcl2 phosphorylation but completely blocks OA-induced Bcl2 phosphorylation in cells expressing DN-JNK1, this supports the conclusion that OA may stimulate Bcl2 phosphorylation via a mechanism involving both JNK1 and ERK1/2. Collectively, these findings indicate a novel role for JNK1 as a SAK and may explain, at least in part, how functional phosphorylation of Bc12 can occur in the absence of growth factor.
 ...
PMID:Novel role for JNK as a stress-activated Bcl2 kinase. 1132 15

Apoptosis plays a central role in shaping the repertoire of circulating mature B lymphocytes, but the underlying molecular mechanisms regulating B cell fate are not well understood. Human B104 B lymphoma cells undergo apoptosis after surface Ig (sIg)M, but not sIgD, ligation; sIgM-mediated apoptosis of B104 cells apparently requires new gene transcription because actinomycin D can inhibit the apoptotic response. Here we report that expression of Bik, a proapoptotic member of the Bcl-2 family, is greatly increased after sIgM ligation. Bik expression was tightly controlled at both transcriptional and post-transcriptional levels. Whereas a calcineurin-dependent pathway was essential for Bik mRNA induction, both the phosphatidylinositol 3-kinase (PI3K)- and the calcineurin-dependent pathways were required for the sustained production of Bik protein. Consistent with these findings, sIgD ligation, which leads to the similar calcium mobilization and increases in Bik mRNA, induced only a transient activation of PI3K and did not lead to sustained Bik protein expression. Furthermore, sustained Bik protein expression correlated with B cell apoptosis, as treatment with either a calcineurin inhibitor or PI3K inhibitors blocked both sIgM-mediated sustained Bik protein induction and apoptosis. In addition, sIgM ligation strongly increased the amount of Bik associated with endogenous Bcl-x, but sIgD ligation did not. Studies with caspase inhibitors also revealed that Bik and Bcl-x interacted upstream of caspases in the B cell apoptosis cascade. Thus, Bik protein induction and, subsequently, sequestering of antiapoptotic Bcl-x by Bik may play an important role in regulating B cell apoptosis.
 ...
PMID:Involvement of Bik, a proapoptotic member of the Bcl-2 family, in surface IgM-mediated B cell apoptosis. 1134 19


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>