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)

In our previous study we showed that insulin-like growth factor-I induces a cAMP-response element (CRE) site-containing Bcl-2 promoter through a novel signaling pathway involving mitogen-activated protein kinase kinase 6/p38beta mitogen-activated protein kinase/MAP kinase-activated protein kinase-3/cAMP-response element-binding protein (CREB) (Pugazhenthi, S., Miller, E., Sable, C., Young, P., Heidenreich, K. A., Boxer, L. M., and Reusch, J. E.-B. (1999) J. Biol. Chem. 274, 27529-27535). In the present investigation, we define a second pathway contributing to CREB-dependent up-regulation of Bcl-2 expression as a novel anti-apoptotic function of Akt signaling. To examine the role of Akt on Bcl-2 expression, a series of transient transfections using a luciferase reporter gene driven by the promoter region of Bcl-2 containing a CRE were carried out. Pharmacological inhibition of phosphatidylinositol (PI) 3-kinase, the upstream kinase of Akt, with LY294002 led to a 45% decrease in Bcl-2 promoter activity. The reporter activity was enhanced 2.3-fold by overexpression of active p110 subunit of PI 3-kinase and inhibited 44% by the dominant negative p85 subunit of PI 3-kinase. Cotransfection with 3-phosphoinositide-dependent kinase (PDK1), which is required for the full activation of Akt, resulted in enhanced luciferase activity. Insulin-like growth factor-I-mediated induction of Bcl-2 promoter activity was decreased significantly (p < 0.01) by the dominant negative forms of p85 subunit of PI 3-kinase, PDK1, and Akt. These data indicate that regulation of Bcl-2 expression by IGF-I involves a signaling cascade mediated by PI 3-kinase/PDK1/Akt/CREB. Furthermore, we measured the Bcl-2 mRNA in PC12 cells overexpressing Akt by real-time quantitative reverse transcription-polymerase chain reaction using the TaqMan(TM) fluorogenic probe system. We observed a 2.1-fold increase in Bcl-2 mRNA levels in the Akt cell line compared with control PC12 cells, supporting the observation that enhanced CREB activity by Akt signaling leads to increased Bcl-2 promoter activity and cell survival.
 ...
PMID:Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. 1075 67

Heptachlor, a chlorinated hydrocarbon insecticide, has been considered an environmental contaminant with potential adverse health effects. Exposure to heptachlor may impair immune functions including the inhibition of leukocyte chemotaxis, which causes defects in host defense mechanisms. This study addresses the effects of heptachlor on the cell cycle progression of human lymphocytes. It has been found that addition of heptachlor to cultured lymphocytic cells prevents the cells from progression into the S phase of the cell cycle, with a concomitant accumulation of cells in G1 phase. An accompanying decrease (deactivation) in cyclin-dependent kinase cdk2 and dephosphorylation (activation) of cdc2 was observed. The altered cell cycle progression may trigger the cell's apoptotic potential, as indicated by the reduced amount of Bcl-2 synthesized inside heptachlor-treated cells. The interference of cell cycle progression by heptachlor was also seen with chlordane and toxaphene, two other chlorinated hydrocarbon insecticides.
 ...
PMID:Differential regulation of the major cyclin-dependent kinases, cdk2 and cdc2, during cell cycle progression in human lymphocytes exposed to heptachlor. 1075 37

The present studies were undertaken to analyse the factors regulating TPA-induced apoptosis. Treatment of the monoblastic U-937 cells with the phorbol ester, TPA, was found to induce apoptosis in two distinct phases. In phase I (from 0 to 72 hours following TPA induction), apoptotic cells appeared, despite the expression of high levels of the anti-apoptotic Bcl-2 protein. After 96 h. of TPA treatment (phase II), the percentage of apoptotic cells increased as did the cell differentiation stage. The first phase apoptotic response could be significantly reduced (70%) by treatment with anti-tumor necrosis factor-alpha (TNF-alpha) antibody. TNF-alpha protein required de novo RNA and protein synthesis and was found to be mediated by protein kinase and protein tyrosine kinases. Manganese superoxide dismutase (MnSOD) inhibited, whereas IL-6 increased TPA-induced apoptosis. These findings suggest that both TPA, via TNF-alpha synthesis, exerts its protective function intracellularly by inducing MnSOD production and IL-6 may be an effective adjunct to TNF-alpha in the clinic, increasing the antitumor potency of this cytokine.
 ...
PMID:Autocrine regulation of TPA-induced apoptosis in monoblastic cell-line U-937: role for TNF-alpha, MnSOD and IL-6. 1076 95

p27kip1 and p21cip1 are cyclin-dependent kinase (cdk) inhibitors which along with p53 play critical roles in the control of cell cycle progression. Accumulation of p27kip1 in post-mitotic neurons is a major event of neurogenesis. We hypothesized that a dysregulation of the expression of p53 and these cdk inhibitors underlies cellular proliferation in medulloblastomas, and tested this hypothesis by investigating p27kip1, p21cip1, Bcl2 and p53 immunoreactivity in 14 medulloblastoma tumors. We noted an inverse relationship between p27kip1 expression and cellular proliferation (MIB1). Focal islands of neuroblastic or glial differentiation expressed high levels of p27kip1, while the undifferentiated, highly-proliferative population of tumor cells showed no detectable p27kip1 expression, thus suggesting a role for p27kip1 in cell cycle control in medulloblastoma. In addition, there was no detectable p21cip1 expression in any of the medulloblastomas studied. The low level of apoptosis displayed by these tumors was not associated with the expression of Bcl-2. A significant relationship was found between detection of p53 protein and poor survival. Since, p21cip1 and p27kip1 are often co-expressed with other INK4 family of cdk inhibitors during the induction of cellular differentiation and are synergistic in their effect, a deregulation of their coordinate expression may underlie the lack of complete differentiation in medulloblastoma.
 ...
PMID:Expression of p27kip1 and p53 in medulloblastoma: relationship with cell proliferation and survival. 1078 68

A series of bisindolylmaleimide (Bis) compounds were designed as analogs of the natural compound staurosporine (STS), which is a potent inducer of apoptosis. Many of the Bis analogs appear to be highly selective inhibitors of the protein kinase C (PKC) family, including PKC-alpha, -beta, -gamma, -delta, -epsilon, and -zeta, unlike STS, which is an inhibitor of a broad spectrum of protein kinases. In this report we describe the effects of the Bis analogs, Bis-I, Bis-II, Bis-III and Ro-31-8220 on the survival and proliferation of HL-60 cells, which have been widely used as a model cell system for studying the biological roles of PKC. Treatment of HL-60 cells with Bis-I, Bis-II, Bis-III, or Ro-31-8220 blocked phosphorylation of the PKC target protein Raf-1 with equal potency but did not appear to affect the general phosphorylation of proteins by other kinases. However, the biological effects of the Bis compounds were different: Bis-I and Bis-II had no observable effects on either cell survival or proliferation; Bis-III inhibited cell proliferation but not survival, whereas Ro-31-8220 induced apoptosis. These results indicated that the members of the PKC family which could be inhibited by the Bis analogs were required neither for survival nor proliferation of HL-60 cells. Analyses of cells treated with Ro-31-8220 showed that the apoptotic effect of Ro-31-8220 on HL-60 cells was mediated by a well-characterized transduction process of apoptotic signals: i.e., mitochondrial cytochrome c efflux and the activation of caspase-3 in the cytosol. Moreover, the ability of Ro-31-8220 to induce apoptotic activation was completely inhibited by the over-expression of the apoptotic suppressor gene, Bcl-2, in the cells. Interestingly, proliferation of the Bcl-2-over-expressing cells was still sensitive to the presence of Ro-31-8220, suggesting that the inhibitory effects of Ro-31-8220 on viability and cell proliferation were mediated by different mechanisms. In particular, the apoptotic effect of Ro-31-8220 on cells was not altered by the presence of an excess amount of the other Bis analogs, suggesting that this effect is mediated by a factor(s) other than PKC or by a mechanism which was not saturable by the other Bis analogs. Finally, structure-function analyses of compounds related to Ro-31-8220 revealed that a thioamidine prosthetic group in Ro-311-8220 was largely responsible for its apoptotic activity.
 ...
PMID:The staurosporine analog, Ro-31-8220, induces apoptosis independently of its ability to inhibit protein kinase C. 1082 75

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.
 ...
PMID:Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. 1083 73

The purpose of the present study was to investigate the mechanisms involved in the induction of apoptosis in newborn cultured cardiomyocytes by activation of adenosine (ADO) A3 receptors and to examine the protective effects of beta-adrenoceptors. The selective agonist for A3 ADO receptors Cl-IB-MECA (2-chloro-N6-iodobenzyl-5-N-methylcarboxamidoadenosine) and the antagonist MRS1523 (5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpy rid ine-5-carboxylate) were used. High concentrations of the Cl-IB-MECA (> or = 10 microM) agonist induced morphological modifications of myogenic cells, such as rounding and retraction of cell body and dissolution of contractile filaments, followed by apoptotic death. In addition, Cl-IB-MECA caused a sustained and reversible increase in [Ca2+]i, which was prevented by the selective antagonist MRS1523. Furthermore, MRS1523 protected the cardiocytes if briefly exposed to Cl-IB-MECA and partially protected from prolonged (48 h) agonist exposure. Apoptosis induced by Cl-IB-MECA was not redox-dependent, since the mitochondrial membrane potential remained constant until the terminal stage of cell death. Cl-IB-MECA activated caspase-3 protease in a concentration-dependent manner after 7 h of treatment and more effectively after 18 h of exposure. Bcl-2 protein was readily detected in control cells, and its expression was significantly decreased after 24 and 48 h of treatment with Cl-IB-MECA. Beta-adrenergic stimulation antagonized the pro-apoptotic effects of Cl-IB-MECA, probably through a cAMP/protein kinase A-independent mechanism, since addition of dibutyryl-cAMP did not abolish the apoptosis induced by Cl-IB-MECA. Incubation of cultured myocytes with isoproterenol (5 microM) for 3 or 24 h almost completely abolished the increase in [Ca2+]i. Prolonged incubation of cardiomyocytes with isoproterenol and Cl-IB-MECA did not induce apoptosis. Our data suggest that the apoptosis-inducing signal from activation of adenosine A3 receptors (or counteracting beta-adrenergic signal) leads to the activation of the G-protein-coupled enzymes and downstream pathways to a self-amplifying cascade. Expression of different genes within this cascade is responsible for orchestrating either cardiomyocyte apoptosis or its protection.
 ...
PMID:Induction of apoptosis in rat cardiocytes by A3 adenosine receptor activation and its suppression by isoproterenol. 1085 59

The interaction of BAD (Bcl-2/Bcl-X(L)-antagonist, causing cell death) with Bcl-2/Bcl-X(L) is thought to neutralize the anti-apoptotic effects of the latter proteins, and may represent one of the mechanisms by which BAD promotes apoptosis. A variety of survival signals are reported to induce the phosphorylation of BAD at Ser(112) or Ser(136), triggering its dissociation from Bcl-2/Bcl-X(L). Ser(136) is thought to be phosphorylated by protein kinase B (PKB, also called Akt), which is activated when cells are exposed to agonists that stimulate phosphatidylinositol 3-kinase (PI3K). In contrast, Ser(112) is reported to be phosphorylated by mitogen-activated protein (MAP) kinase-activated protein kinase-1 (MAPKAP-K1, also called RSK) and by cAMP-dependent protein kinase (PKA). Here we identify Ser(155) as a third phosphorylation site on BAD. We find that Ser(155) is phosphorylated preferentially by PKA in vitro and is the only residue in BAD that becomes phosphorylated when cells are exposed to cAMP-elevating agents. The phosphorylation of BAD at Ser(155) prevents it from binding to Bcl-X(L) and promotes its interaction with 14-3-3 proteins. We also provide further evidence that MAPKAP-K1 mediates the phosphorylation of Ser(112) in response to agonists that activate the classical MAP kinase pathway. However insulin-like growth factor 1, a potent activator of PI3K and PKB does not increase the phosphorylation of Ser(136) in BAD-transfected HEK-293 cells, and nor is the basal level of Ser(136) phosphorylation suppressed by inhibitors of PI3K.
 ...
PMID:Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a novel site, Ser155. 1088 Mar 54

Lack of selectivity in the killing of tumor and normal cells is a major obstacle in cancer therapy. By inhibiting normal but not autonomous cell growth, we exploited the differences in cell cycle regulation to achieve a selective protection of nonautonomous cells against paclitaxel and other microtubule-active drugs. Tubulin polymerization, a primary effect of paclitaxel, can be dissociated from Bcl-2 phosphorylation and cytotoxicity in HL-60 cells. Growth arrest prevented paclitaxel-induced Bcl-2 phosphorylation and apoptosis without affecting paclitaxel-induced tubulin polymerization. We abrogated the effects of paclitaxel on MCF-10A immortalized breast cells, while preserving its effects on MCF-7 cancer cells. Unlike MCF-7 cells, MCF-10A cells were arrested by epidermal growth factor withdrawal, precluding paclitaxel-induced Bcl-2 phosphorylation. Furthermore, the inhibition of the epidermal growth factor receptor kinase with low doses of AG1478 arrested growth of MCF-10A but not MCF-7 cells. Pretreatment with AG1478 did not affect paclitaxel-induced Bcl-2/Raf-1 phosphorylation in MCF-7 but abrogated such phosphorylation in MCF-10A. Exploitation of growth factor dependency may allow the protection of normal cells from microtubule-active drugs.
 ...
PMID:Loss of cell cycle control allows selective microtubule-active drug-induced Bcl-2 phosphorylation and cytotoxicity in autonomous cancer cells. 1091 51

Microtubule-damaging agents arrest cells at G(2)/M and induce apoptosis in association with phosphorylation of the anti-apoptotic proteins Bcl-2 and Bcl-X(L). Because microtubule inhibitors activate JNK, we sought to determine whether JNK was responsible for Bcl-2/Bcl-X(L) phosphorylation in KB-3 cells treated with vinblastine. Two major endogenous forms of JNK, p46(JNK1) and p54(JNK2), were present in KB-3 cells, and both isoforms were activated by vinblastine as determined by Mono Q chromatography. We used antisense oligonucleotides (AS) to specifically inhibit their expression. A combination of AS-JNK1 with AS-JNK2 inhibited by 80% vinblastine-induced phosphorylation of two known JNK substrates, c-Jun and ATF-2. In addition, AS-JNK1/2 inhibited vinblastine-induced phosphorylation of Bcl-2 by 85% and that of Bcl-X(L) by 65%. Stable expression of the JNK scaffold protein JIP-1 blocked vinblastine-induced phosphorylation of c-Jun and ATF-2, but did not affect Bcl-2/Bcl-X(L) phosphorylation, confirming a bifurcation in JNK signaling involving both nuclear and non-nuclear substrates. Vinblastine-induced phosphorylation of Raf-1 was unaffected by AS-JNK1/2 and was associated with loss of activity for MEK substrate in vitro and inactivation of ERK in vivo. These results provide evidence for a direct role of the JNK pathway in apoptotic regulation through Bcl-2/Bcl-X(L) phosphorylation.
 ...
PMID:Vinblastine-induced phosphorylation of Bcl-2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade. 1091 35


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