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 mechanism of lovastatin-induced cell death was examined in three established human glioblastoma cell lines; U87, U251, and U138. Changes in potential modifiers of apoptosis, including Bcl-2 family proteins and MAP kinase targets after such lovastatin treatment, were evaluated. Lovastatin (5 microm) treatment causes extensive cell death in two of the cell lines, U87 and U251; but only minimal in a third, U138. Lovastatin-induced death occurs in correlation with significantly increased levels of the BH3-only protein, Bim. The up-regulation of Bim levels was directly associated with an increased incidence of apoptosis. Lovastatin treatment in U87 cells results in activation of targets of three major mitogen-activating protein kinase cascades including Erk1/2, JNK and p38. Changes in levels of Bim, as well as increase phosphorylation of Erk1/2, c-jun, and p38 are all prevented by co-incubation of lovastatin and the isoprenylation metabolite, geranylgeranyl pyrophosphate. Inhibition of the MAP kinase pathways failed to block the increased expression of Bim expression or cell death. Further elucidation of the mechanisms of lovastatin-induced up-regulation of Bim and apoptosis in glioblastoma cells are important in determining a potential role for lovastatin as a chemotherapy agent.
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PMID:Lovastatin-induced up-regulation of the BH3-only protein, Bim, and cell death in glioblastoma cells. 1503 Apr 1

Apoptosis is implicated in the progressive cell loss and fibrosis both at glomerular and tubulointerstitial level. In this study, we examined the potential mechanisms by which persistent proteinuria (protein-overload model) could induce apoptosis. After uninephrectomy (UNX), Wistar rats received daily injections of 0.5 g of bovine serum albumin (BSA)/100 g body weight or saline. Both at day 8 and day 28, rats receiving BSA had proteinuria and renal lesions characterized by tubular atrophy and/or dilation and mononuclear cell infiltration. In relation to control-UNX rats, renal cortex of nephritic rats showed an increment in AT2 mRNA (reverse transcriptase-polymerase chain reaction) and protein (Western blot) expression. In both groups, AT2 receptor immunostaining was mainly localized in proximal tubular cells. Rats with persistent proteinuria showed a significantly increased number of terminal dUTP nick-end labeling positive apoptotic cells compared with UNX-controls, both in glomeruli and tubulointerstitium. Double staining for apoptosis and AT2 receptor showed that most terminal dUTP nick-end labeling positive cells were found in tubules expressing AT2 receptor. Using an antibody that recognizes the active form caspase-3, we observed an increment in caspase-3 activation in rats receiving BSA with respect to those receiving saline. Rats with persistent proteinuria showed a diminution in the phosphorylation of Bcl-2 with respect to UNX-controls both at day 8 and day 28. By contrast, no changes were observed either in the Bax or in the Bcl-2 protein levels. The administration of BSA to UNX rats induced a diminution in the phosphorylation of ERK with respect to UNX-control at all times studied. The changes observed in ERK activities took place without alterations of ERK1/2 protein levels. In summary, our data suggest that persistent proteinuria causes apoptosis in tubular cells through the activation of AT2 receptor, which can, in turn, inhibit MAP kinase (ERK1/2) activation and Bcl-2 phosphorylation.
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PMID:Persistent proteinuria up-regulates angiotensin II type 2 receptor and induces apoptosis in proximal tubular cells. 1511 28

Bcl-2 protein play important roles in the regulation of apoptosis. We previously reported that the phosphorylation of Bcl-2 was augmented by treatment with protein phosphatase 2A (PP2A) inhibitor; however, the kinase responsible for Bcl-2 phosphorylation had not yet been identified. In this study, we identified extracellular-signal-regulated kinase (ERK) as the responsible kinase for the phosphorylation of Bcl-2. We also found that the transmembrane region (TM) deleted form of Bcl-2 (Bcl-2DeltaTM), which was unable to localize on the mitochondria was constitutively phosphorylated, whereas wild-type Bcl-2 that localized on the mitochondria, was present in its hypophosphorylated form. The phosphorylation of Bcl-2DeltaTM was retarded by treatment with MAP kinase ERK kinase (MEK) inhibitor and PP2A did not bind to Bcl-2DeltaTM. These observations suggest that Bcl-2DeltaTM is constitutively phosphorylated by ERK, but is not dephosphorylated by PP2A in human tumor cell lines. The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.
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PMID:The phosphorylation status and anti-apoptotic activity of Bcl-2 are regulated by ERK and protein phosphatase 2A on the mitochondria. 1522 43

The aim of this study was to elucidate the role of JNK signaling pathway involved in tumor necrosis factor-alpha (TNF-alpha)-induced death of chondrocytes. Primary chondrocyte cultures were obtained from human knee osteoarthritis cartilages. First passage chondrocytes were treated with TNF-alpha and various potentiators, and cell death was measured with MTT assay. C-Jun N terminal kinase (JNK) activation was investigated with the solid phase kinase assay. Expression of apoptosis-related molecule was assayed with Western blot. Chondrocytes were resistant to TNF-alpha-induced cell death. In contrast, pretreatment with actinomycin D, the phosphatase inhibitor vanadate or MAP kinase phosphatase-1 (MKP-1) inhibitor Ro318220 invariably led to chondrocyte death. While TNF-alpha alone stimulated a single, brief JNK activity, a second JNK peak was observed when the cells were pretreated with actinomycin D. When the cells were pretreated with vanadate or Ro318220, TNF-alpha-induced JNK activation was greatly prolonged, which was associated with the induction of cell death. The expression of Bcl-2 and Mcl-1 decreased significantly in conditions of cell death. In conclusions, our data suggest that chondrocyte death induced by TNF-alpha is associated with sustained JNK activation. This effect may be due to downregulation of TNF-alpha induced phosphatase that inactivates JNK and of Bcl-2 family proteins.
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PMID:Prologation of c-Jun N-terminal kinase is associated with cell death induced by tumor necrosis factor alpha in human chondrocytes. 1530 49

Transcription factor NGFI-B (neuronal growth factor-induced clone B), also called Nur77 or TR3, is an immediate early gene and an orphan member of the nuclear receptor family. The NGFI-B protein also has a function distinct from that of a transcription factor; it translocates to mitochondria to initiate apoptosis. Recently, it was demonstrated that NGFI-B interacts with Bcl-2 by inducing a conformational change in Bcl-2, converting it from protector to a killer. After exposing rat cerebellar granule neurons to glutamate (100 mum, 15 min), NGFI-B translocated to the mitochondria. Growth factors such as the epidermal growth factor activate the MAP kinase ERK, the activity of which may determine whether a cell survives or undergoes apoptosis. In the present study we found that the epidermal growth factor activated ERK2 in cerebellar granule neurons and that this activation prohibited glutamate-induced subcellular translocation of NGFI-B. Likewise, overexpressed active ERK2 resulted in a predominant nuclear localization of green fluorescent protein-tagged NGFI-B. Thus, activation of ERK2 may overcome apoptosis-induced subcellular translocation of NGFI-B. This finding represents a novel and rapid growth factor survival pathway that is independent of gene regulation.
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PMID:ERK2 prohibits apoptosis-induced subcellular translocation of orphan nuclear receptor NGFI-B/TR3. 1544 59

Mitochondria are involved directly in cell survival and death. The assumption has been made that drugs that protect mitochondrial viability and prevent apoptotic cascade-induced mitochondrial permeability transition pore (MPTp) opening will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor anti-Parkinson drug. Unlike selegiline, it is not derived from amphetamine, and is not metabolized to neurotoxic L-methamphetamine derivative. In addition, it does not have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to levodopa for patients with early and late Parkinson's disease (PD) and adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Phase III controlled studies indicate that it might have a disease-modifying effect in PD that may be related to its neuroprotective activity. Its S isomer, TVP1022, is more than 1,000 times less potent as an MAO inhibitor. Both drugs, however, have neuroprotective activity in neuronal cell cultures in response to various neurotoxins, and in vivo in response to global ischemia, neurotrauma, head injury, anoxia, etc., indicating that MAO inhibition is not a prerequisite for neuroprotection. Their neuroprotective effect has been demonstrated to be associated directly with the propargylamine moiety, which protects mitochondrial viability and MTPp by activating Bcl-2 and protein kinase C (PKC) and by downregulating the proapoptotic FAS and Bax protein families. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective, neurotrophic, soluble APP alpha (sAPPalpha) by PKC- and MAP kinase-dependent activation of alpha-secretase. The identification of the propargylamine moiety as the neuroprotective component of rasagiline has led us to development of novel bifunctional anti-Alzheimer drugs (ladostigil) possessing cholinesterase and brain-selective MAO inhibitory activity and a similar neuroprotective mechanism of action.
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PMID:Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. 1557 6

Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD. However, the answer to the question of how Raf-1 is normally lured to the mitochondria and becomes activated remains elusive. p21-activated protein kinases (Paks) are serine/threonine protein kinases that phosphorylate Raf-1 at Ser-338 and Ser-339. Here we elucidate the molecular mechanism through which Pak1 signals to BAD through a Raf-1-activated pathway. Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112. Moreover, the mitochondrial translocation of Raf-1 and the interaction between Raf-1 and Bcl-2 are regulated by Raf-1 phosphorylation at Ser-338/Ser-339. Notably, we show that formation of a Raf-1-Bcl-2 complex coincides with loss of an interaction between Bcl-2 and BAD. These signals are specific for Pak1, because Src-activated Raf-1 only stimulates the MAP kinase cascade. Thus, our data identify the molecular connections of a Pak1-Raf-1-BAD pathway that is involved in cell survival signaling.
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PMID:p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association. 1584 94

The mitochondria are directly involved in cell survival and death. Drugs that protect mitochondria viability and prevent apoptotic cascade mechanisms involved in mitochondrial permeability transition pore (MPTp) will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor, anti-Parkinson drug. Unlike selegiline, rasagiline is not derived from amphetamine, is not metabolized to neurotoxic l-methamphetamine derivative, nor does it have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to L-dopa for patients with early and late Parkinson's disease (PD), and adverse events do not occur with greater frequency in subjects receiving rasagiline than those on placebo. Controlled studies indicate that it might have a disease-modifying effect in PD that may be related to neuroprotection. Its S-isomer, TVP1022, is a relatively inactive MAO inhibitor. However, both drugs have similar neuroprotective activities in neuronal cell cultures in response to various neurotoxins and in vivo (global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a pre-requisite for neuroprotection. Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha) by PKC and MAP kinase-dependent activation of alpha-secretase. The neuroprotective activity of propargylamine has led us to develop novel bifunctional neuroprotective iron-chelating MAO-inhibiting drugs possessing propargyl moiety for the treatment of other neurodegenerative diseases.
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PMID:Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. 1585 Jun 77

Smoking is a major cause of human lung cancer. Past studies suggest that apoptosis might influence the malignant phenotype, but little is known about the association between apoptosis and cigarette smoke (CS)-induced lung pathogenesis. Using an in situ cell death detection kit (TA300), the association of CS with apoptosis was determined in a concentration-dependent manner. Furthermore, the expression of related proteins were investigated in the terminal bronchiole areas of the lung tissue from rats exposed to CS. Results showed that the expression of phosphotyrosine proteins was increased significantly in lung tissue of rats exposed to CS from 5 to 15 cigarettes. Using Western blotting and immunoprecipitation assay, Fas, a death receptor, was proved just be one of these phosphotyrosine proteins. CS triggered activation of MAP kinase (p38/JNK or ERK2) pathway, which led to Jun or p53 phosphorylation and FasL induction links Fas phosphorylation. Further, smoke treatment produced an increase in the level of proapoptotic proteins (Bax, t-Bid, cytochrome c and caspase-3), but a decline in Bcl-2, procaspase-8 and procaspase-9 proteins. Thus, CS-induced apoptosis may result from two main mechanisms, one is the activation of p38/JNK-Jun-FasL signaling, and the other is stimulated by the stabilization of p53, increase in the ratio of Bax/Bcl-2, release of cytochrome c; thus, leading to activation of caspase cascade.
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PMID:Induction of apoptosis in the lung tissue from rats exposed to cigarette smoke involves p38/JNK MAPK pathway. 1597 Feb 77

Depletion of mitochondrial DNA (mtDNA) or treatment with mitochondrial poison CCCP initiates mitochondrial stress signaling, which operates through altered Ca2+ homeostasis. In C2C12 rhabdomyoblasts and A549 human lung carcinoma cells mitochondrial stress signaling activates calcineurin and a number of Ca2+ responsive factors including ATF, NFAT, CEBP/delta and CREB. Additionally, PKC and MAP kinase are also activated. A number of nuclear gene targets including those involved in Ca2+ storage/release (RyR1, calreticulin, calsequestrin), glucose metabolism (hexokinase, pyruvate kinase, Glut4), oncogenesis (TGFbeta1, cathepsin L, IGFR1, melanoma antigen) and apoptosis (Bcl-2, Bid, Bad, p53) are upregulated. Mitochondrial stress in both C2C12 myoblasts and A549 cells induced morphological changes and invasive phenotypes. These cells also showed markedly increased resistance to etoposide-induced apoptosis that is a hallmark of highly invasive tumors. Our results describe a new mechanism of altered nuclear gene expression and phenotypic changes triggered by mitochondrial dysfunction and mtDNA damage.
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PMID:Mitochondria-to-nucleus stress signaling in mammalian cells: nature of nuclear gene targets, transcription regulation, and induced resistance to apoptosis. 1597 49


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