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)

Intact endothelium acts as a sensor and transducer of signals and also provides a nonthrombogenic surface at the blood-vascular wall interface. Hence, mechanisms that maintain the integrity of the endothelium are of interest in physiological and pathological states. In this study we show that apoptosis induced by growth factor and serum deprivation of endothelial cells occurs at all phases of the cell cycle and can be blocked by fibroblast growth factor-2 (FGF-2) independently of its mitogenic activity. As the Bcl-2 family of proteins plays a prominent role in regulating cell survival, we attempted to identify Bcl-2 homologues expressed in endothelial cells. Here we demonstrate that, in addition to the previously identified A1, four other members of the Bcl-2 family, Bcl-2, Mcl-1, Bcl-X(L), and Bax, are expressed in endothelial cells. Of these family members, only Bcl-2 is induced by FGF-2. Overexpression of Bcl-2, using a retroviral vector, protects endothelial cells from serum and growth factor deprivation. There is no difference in FGF-2-induced proliferation between Bcl-2-overexpressing cells and those transduced with the empty retroviral vector. At early time points Bcl-2 is not up-regulated, but FGF-2 still has a protective effect. However, FGF-2 protects only adherent endothelial cells but not those that are cultured in suspension. The early effect of FGF-2 is dependent on tyrosine phosphorylation but not on activation of the MAP kinase pathway. Thus, FGF-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms.
Am J Pathol 1997 Dec
PMID:Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. 940 28

Programmed cell death (apoptosis) is a controlled process by which unwanted cells are selectively eliminated. Several families of proteins including the Bcl-2, tumor necrosis factor receptor 1, and caspase families play essential roles in the regulation, signaling, and execution of the genetic cell death program. The recently described three-dimensional structures of members of these families elucidate the structural basis of their functions and provide insights into the mechanisms by which these proteins regulate apoptosis.
J Mol Biol 1997 Dec 05
PMID:Three-dimensional structures of proteins involved in programmed cell death. 940 39

The reaper protein of Drosophila melanogaster has been shown to be a central regulator of apoptosis in that organism. However, it has not been shown to function in any vertebrate nor have the cellular components required for its action been defined. In this report we show that reaper can induce rapid apoptosis in vitro using an apoptotic reconstitution system derived from Xenopus eggs. Moreover, we show that a subcellular fraction enriched in mitochondria is required for this process and that reaper, acting in conjunction with cytosolic factors, can trigger mitochondrial cytochrome c release. Bcl-2 antagonizes these effects, but high levels of reaper can overcome the Bcl-2 block. These results demonstrate that reaper can function in a vertebrate context, suggesting that reaper-responsive factors are conserved elements of the apoptotic program.
EMBO J 1997 Dec 15
PMID:Reaper-induced apoptosis in a vertebrate system. 940 66

Normal human keratinocytes synthesize and release nerve growth factor (NGF) and express both the low- and the high-affinity NGF receptor. Because NGF has been shown to rescue certain cell types from programmed cell death, we investigated the role of endogenous NGF in preventing keratinocyte apoptosis. We report here that apoptosis is induced in normal human keratinocytes in culture by blocking endogenous NGF signaling with either anti-NGF neutralizing antibody or K252, a specific inhibitor of the tyrosine kinase high-affinity NGF receptor. Apoptosis was assessed by DNA laddering, electron microscopy, and in situ nick end labeling technique. In anti-NGF-treated keratinocytes, the apoptotic process starts at 96 h, and is maximal at 120 h. After K252 treatment, apoptosis starts at 48 h and peaks at 120 h. Because the product of the bcl-2 proto-oncogene protects many cell types from apoptosis, we measured the levels of this protein in apoptotic keratinocytes. We found that both K252 and anti-NGF antibody strikingly downregulate bcl-2 expression, starting at 72 h. Furthermore, HaCat keratinocytes stably transfected with a plasmid containing bcl-2 cDNA fail to undergo apoptosis when treated with K252. These findings show that autocrine NGF acts as a survival factor for human keratinocytes in vitro through its high-affinity NGF receptor, possibly by maintaining constant levels of Bcl-2.
J Invest Dermatol 1997 Dec
PMID:Autocrine nerve growth factor protects human keratinocytes from apoptosis through its high affinity receptor (TRK): a role for BCL-2. 940 17

The expression of two autoimmune thyroid diseases. GD and idiopathic myxoedema, is associated with antibodies to the thyroid-stimulating hormone (TSH) receptor. Thyroid stimulating antibodies (TSAb) in GD are TSH agonists and cause hyperthyroidism as well as goitre, whereas thyroid stimulation blocking antibodies (TSBAb) in idiopathic myxoedema are TSH antagonists and cause hypothyroidism and thyroid atrophy. We investigated the effect of antibodies to TSH receptor on Fas-mediated apoptosis of thyroid epithelial cells (thyrocytes). Human IgG was isolated from healthy donors, patients with GD and idiopathic myxoedema. Human thyrocytes were obtained from surgical specimens. Thyrocytes were cultured in the presence or absence of human IgG with or without interferon-gamma (IFN-gamma) or IL-1beta for a specified time. After incubation, we examined the level of cAMP in cultured supernatants and both Fas and Bcl-2 expression on thyrocytes. In addition, we examined anti-Fas-mediated apoptosis of thyrocytes. Fas expression on thyrocytes was significantly down-regulated by Graves' IgG and TSH, although idiopathic myxoedema IgG did not affect Fas expression on thyrocytes. Idiopathic myxoedema IgG abrogated the effect of TSH on both cAMP production and inhibition of Fas expression on thyrocytes. Treatment of thyrocytes with IL-1beta or IFN-gamma caused a marked augmentation of Fas expression on thyrocytes. The increase of Fas expression of thyrocytes induced by IL-1beta or IFN-gamma was significantly suppressed in the presence of TSH or Graves' IgG. Anti-Fas-induced apoptosis of thyrocytes was observed in thyrocytes treated with IL-1beta or IFN-gamma, but was markedly inhibited in the presence of TSH or Graves' IgG. Furthermore, idiopathic myxoedema IgG abrogated most of the inhibitory effect of TSH on Fas-mediated apoptosis of thyrocytes treated with IL-1beta or IFN-gamma. Bcl-2 expression of thyrocytes did not change after stimulation with TSH, Graves' IgG, idiopathic myxoedema IgG, IL-1beta or IFN-gamma. These results suggest that TSAb found in Graves' patients may be potentially involved in the development of goitre by inhibition of Fas-mediated apoptosis of thyrocytes. In addition, TSBAb inhibit the action of TSH and increase the sensitivity toward Fas-mediated apoptosis of thyrocytes, inducing thyroid atrophy seen in patients with idiopathic myxoedema.
Clin Exp Immunol 1997 Dec
PMID:Modulation of Fas-mediated apoptosis of human thyroid epithelial cells by IgG from patients with Graves' disease (GD) and idiopathic myxoedema. 940 48

p27KiP1, a member of the Cip/Kip family of cyclin-dependent kinase (cdk) inhibitors, has been implicated in mediating G1 arrest in response to a variety of growth inhibitory signals. Its importance in regulating cell growth is emphasized by the fact that mice lacking p27Kip1 are abnormally large and display hyperplasia of multiple tissues. However, these mice retain the ability to undergo G1 arrest in response to growth inhibitory signals, suggesting that p27KiP1 may serve other functions important for controlling tissue growth. In the present study, we utilized an adenoviral vector-based expression system to examine the consequences of p27Kip1 overexpression in the human carcinoma cell lines A549, HeLa and RKO, in human melanoma SK-MEL-110 cells, in human lung fibroblasts IMR90 and in the rat fibroblast line Rat1. We demonstrate that overexpression of p27Kip1 leads to apoptotic cell death in all cell types, and further show that ectopic expression of Bcl-2 can protect HeLa cells from apoptosis mediated by p27Kip1 overexpression. To our knowledge, this is the first study demonstrating that p27Kip1 can induce apoptosis. Our findings provide new insight into the possible functions of this growth regulatory protein, and support the potential utility of gene therapeutic approaches aimed at elevating p27Kip1 expression for treatment of human cancers.
Oncogene 1997 Dec 11
PMID:p27Kip1 overexpression causes apoptotic death of mammalian cells. 941 43

Bcl-2 is an integral membrane oncoprotein that localizes to membranes of the mitochondria, endoplasmic reticulum, and nuclear envelope. Bcl-2 is a member of a family of cell death regulators and functions to inhibit apoptosis. Using confocal microscopy and immunoblotting we show that the ability of bcl-2 to suppress cell death following genotoxic damage can be a consequence of inhibiting nuclear import of induced wild-type p53 protein. Our data suggests that the ability of bcl-2 to modulate trafficking events is not cell type specific. These data support a 'gatekeeper' mechanism for cell death suppression by bcl-2.
Oncogene 1997 Dec 04
PMID:Bcl-2 inhibits p53 nuclear import following DNA damage. 941 67

Transient elevation of cytosolic Ca2+ induces the expression of a variety of genes involved in cell growth and transformation, including the early response gene c-fos. Previously, we reported that Bcl-2 inhibits the transient elevation of cytosolic Ca2+ induced by thapsigargin (TG), a selective inhibitor of the endoplasmic reticulum-associated Ca2+-ATPase. Therefore, to determine if the effect of Bcl-2 on cytosolic Ca2+ elevation modulates Ca2+ signaling, we investigated the induction of c-fos by TG in WEHI7.2 mouse lymphoma cells, control transfectants (WEHI7.2-neo), and transfectants that stably express a high level of Bcl-2 (W.Hb12 and W.Hb15). TG induced 20-fold elevation of c-fos mRNA in WEHI7.2 and WEHI7.2-neo cells, but c-fos mRNA induction by TG was only fivefold in W.Hb12 and W.Hb15 cells. In contrast, phorbol 12-myristate acetate induced marked c-fos mRNA elevation in both WEHI7.2 and W.Hb12 cells, indicating that the inhibitory effect of Bcl-2 is selective for induction of c-fos by Ca2+. To measure c-fos promoter activity, WEHI7.2 and W.Hb12 cells were transiently transfected with a c-fos promoter-luciferase reporter plasmid. TG induced c-fos promoter activity in WEHI7.2 cells, but not in W.Hb12 cells. In WEHI7.2 cells, the signal for c-fos induction by TG was cytosolic Ca2+ elevation, as the increase in both c-fos mRNA level and promoter activity were prevented by lowering extracellular Ca2+ concentration, a condition that inhibits cytosolic Ca2+ elevation by reducing the TG-mobilizable Ca2+ pool. In summary, the findings indicate that Bcl-2 regulates Ca2+ signaling.
Oncogene 1997 Dec 04
PMID:Bcl-2 inhibits c-fos induction by calcium. 941 76

1. Activation of alpha1-adrenoceptor stimulation regulates eicosanoid metabolism and growth in vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the functional implications of lipoxygenase pathway in alpha1-adrenoceptor-stimulated VSMCs growth through mutually exclusive biological functions, that is cell proliferation and cell death. 2. Phenylephrine (10 microM), a specific alpha1-adrenoceptor agonist, enhanced [3H]-thymidine incorporation by 300% above basal. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, caused 36 and 50% decrease in phenylephrine (10 microM)-stimulated [3H]-thymidine incorporation at concentrations of 1 microM and 10 microM respectively. 3. Inversely, treatment of phenylephrine (10 microM)-stimulated VSMCs with NDGA induced DNA fragmentation in a dose-dependent fashion. The level of induction of DNA fragmentation by NDGA was 225, 319 and 406% above the phenylephrine (10 microM)-level at concentrations of 0.1 microM, 1 microM and 10 microM, respectively. This induction of DNA fragmentation was partially prevented by exogenous 15-hydroxyeicosatetraenoic acid (15-HETE). The inhibition of apoptosis was 53 and 63% at concentrations of 5 microM and 10 microM of 15HETE, respectively, as compared with phenylephrine (10 microM) in the presence of NDGA (10 microM). 4. Furthermore, we performed the time-course analysis of Bcl-2 protein expression in phenylephrine (10 microM)-stimulated VSMCs. The expression of Bcl-2 protein disappeared after a 2 h incubation in the presence of NDGA (10 microM), but remained stable after a 2 h incubation period in the absence of NDGA (10 microM). 5, These results suggest that the lipoxygenase pathway is involved in cell proliferation by preventing apoptosis through the level of Bcl-2 protein expression.
Br J Pharmacol 1997 Dec
PMID:The regulation of mitogenesis and apoptosis in response to the persistent stimulation of alpha1-adrenoceptors: a possible role of 15-lipoxygenase. 942 4

Expression of Bcl-2, a programmed cell death (PCD)-suppressing molecule, and Bax, the Bcl-2 related PCD-accelerating protein was investigated in varied human brain tumors. Thirty-six cases of human brain tumors comprising 4 astrocytomas, 3 anaplastic astrocytomas, 4 glioblastomas multiforme, 5 medulloblastomas, 1 ependymoma, 2 choroid plexus papilloma, 1 ganglioglioma, 1 central neurocytoma, 4 meningotheliomatous meningiomas, 3 transitional meningiomas, 4 fibroblastic meningiomas, 3 acoustic neurinomas and 1 craniopharyngioma were analyzed for the localization of Bax and Bcl-2 proteins. No relationship between the degree of the histological malignancy and the presence of Bax or Bcl-2 proteins was found in varied human brain tumors. However, it is suggested that reduced expression of Bax protein is necessary for the malignant transformation and progression of the brain tumors, since no histologically malignant brain tumors with positive Bax protein were present. Our findings indicate that the expression pattern of Bax and Bcl-2 may reflect histogenetic difference of each type of brain tumors.
Neurol Res 1997 Dec
PMID:Expression of Bax and bcl-2 proteins, regulators of programmed cell death, in human brain tumors. 942 64


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