scholarly journals Thrombin inhibits Bim (Bcl-2-interacting mediator of cell death) expression and prevents serum-withdrawal-induced apoptosis via protease-activated receptor 1

2003 ◽  
Vol 375 (1) ◽  
pp. 99-109 ◽  
Author(s):  
Claire J. CHALMERS ◽  
Kathryn BALMANNO ◽  
Kathryn HADFIELD ◽  
Rebecca LEY ◽  
Simon J. COOK
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
De Novo ◽  
Fibroblast Cell ◽  
Mitogen Activated Protein Kinase ◽  
Serum Withdrawal ◽  
Mitogen Activated Protein ◽  
Protease Activated Receptor 1 ◽  
Induced Apoptosis ◽  
Ccl39 Cells

To investigate the role of thrombin in regulating apoptosis, we have used CCl39 cells, a fibroblast cell line in which thrombin-induced cell proliferation has been extensively studied. Withdrawal of serum from CCl39 cells resulted in a rapid apoptotic response that was completely prevented by the inclusion of thrombin. The protective effect of thrombin was reversed by pertussis toxin, suggesting that cell-survival signalling pathways are activated via a Gi or Go heterotrimeric GTPase. Serum-withdrawal-induced death required de novo gene expression and was preceded by the rapid de novo expression of the pro-apoptotic ‘BH3-only’ protein Bim (Bcl-2-interacting mediator of cell death). Thrombin strongly inhibited the up-regulation of both Bim protein and Bim mRNA. The ability of thrombin to repress Bim expression, and to protect cells from apoptosis, was reversed by U0126, a MEK1/2 [MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) 1/2] inhibitor, or LY294002, a phosphoinositide 3′-kinase (PI3K) inhibitor, suggesting that both the Raf→MEK→ERK1/2 and PI3K pathways co-operate to repress Bim and promote cell survival. A PAR1p (protease-activated receptor 1 agonist peptide) was also able to protect cells from serum-withdrawal-induced apoptosis, suggesting that thrombin acts via PAR1 to prevent apoptosis.

scholarly journals De Novo Synthesis of Sphingolipids Is Required for Cell Survival by Down-Regulating c-Jun N-Terminal Kinase inDrosophila Imaginal Discs

1999 ◽  
Vol 19 (10) ◽  
pp. 7276-7286 ◽  
Author(s):  
Takashi Adachi-Yamada ◽  
Tomokazu Gotoh ◽  
Isamu Sugimura ◽  
Minoru Tateno ◽  
Yasuyoshi Nishida ◽  
...  
Keyword(s):  
Cell Survival ◽  
Compound Eye ◽  
De Novo ◽  
Imaginal Discs ◽  
Mitogen Activated Protein Kinase ◽  
Serine Palmitoyltransferase ◽  
De Novo Synthesis ◽  
Jnk Pathway ◽  
Activation Of Transcription ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein kinase (MAPK) is a conserved eukaryotic signaling factor that mediates various signals, cumulating in the activation of transcription factors. Extracellular signal-regulated kinase (ERK), a MAPK, is activated through phosphorylation by the kinase MAPK/ERK kinase (MEK). To elucidate the extent of the involvement of ERK in various aspects of animal development, we searched for a Drosophila mutant which responds to elevated MEK activity and herein identified a lace mutant. Mutants with mild lace alleles grow to become adults with multiple aberrant morphologies in the appendages, compound eye, and bristles. These aberrations were suppressed by elevated MEK activity. Structural and transgenic analyses of the lace cDNA have revealed that the lace gene product is a membrane protein similar to the yeast protein LCB2, a subunit of serine palmitoyltransferase (SPT), which catalyzes the first step of sphingolipid biosynthesis. In fact, SPT activity in the fly expressing epitope-tagged Lace was absorbed by epitope-specific antibody. The number of dead cells in various imaginal discs of a lace hypomorph was considerably increased, thereby ectopically activating c-Jun N-terminal kinase (JNK), another MAPK. These results account for the adult phenotypes of thelace mutant and suppression of the phenotypes by elevated MEK activity: we hypothesize that mutation of lace causes decreased de novo synthesis of sphingolipid metabolites, some of which are signaling molecules, and one or more of these changes activates JNK to elicit apoptosis. The ERK pathway may be antagonistic to the JNK pathway in the control of cell survival.

scholarly journals BAFF regulates B cell survival by downregulating the BH3-only family member Bim via the ERK pathway

2005 ◽  
Vol 202 (10) ◽  
pp. 1363-1374 ◽  
Author(s):  
Andrew Craxton ◽  
Kevin E. Draves ◽  
Adriana Gruppi ◽  
Edward A. Clark
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Mitogen Activated Protein Kinase ◽  
Marginal Zone B Cells ◽  
B Cell Survival ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
B Cell Homeostasis ◽  
Induced Apoptosis

The B cell activating factor belonging to the tumor necrosis factor family (BAFF) is required for B cell survival and maturation. The mechanisms by which BAFF mediates B cell survival are less understood. We found that BAFF and a proliferation-inducing ligand (APRIL), which are related, block B cell antigen receptor (BCR)–induced apoptosis upstream of mitochondrial damage, which is consistent with a role for Bcl-2 family proteins. BCR ligation strongly increased expression of the proapoptotic Bcl-2 homology 3–only Bcl-2 protein Bim in both WEHI-231 and splenic B cells, and increases in Bim were reversed by BAFF or APRIL. Small interfering RNA vector–mediated suppression of Bim blocked BCR-induced apoptosis. BAFF also induced Bim phosphorylation and inhibited BCR-induced association of Bim with Bcl-2. BAFF induced delayed but sustained stimulation of extracellular signal–regulated kinase (ERK) and its activators, mitogen-activated protein kinase/ERK activating kinase (MEK) and c-Raf, and MEK inhibitors promoted accumulation and dephosphorylation of Bim. These results suggest that BAFF inhibits BCR-induced death by down-regulating Bim via sustained ERK activation, demonstrating that BAFF directly regulates Bim function. Although transitional immature type 1 (T1) B cell numbers are normal in Bim−/− mice, T2 and follicular mature B cells are elevated and marginal zone B cells are reduced. Our results suggest that mature B cell homeostasis is maintained by BAFF-mediated regulation of Bim.

scholarly journals p38 Mitogen-Activated Protein Kinase Mediates Cell Death and p21-Activated Kinase Mediates Cell Survival during Chemotherapeutic Drug-induced Mitotic Arrest

2003 ◽  
Vol 14 (5) ◽  
pp. 2071-2087 ◽  
Author(s):  
Karl Deacon ◽  
Pratibha Mistry ◽  
Jonathan Chernoff ◽  
Jonathan L. Blank ◽  
Rajnikant Patel
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Cell Survival ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Chemotherapeutic Drugs ◽  
Chemotherapeutic Drug ◽  
Drug Induced ◽  
Mitogen Activated Protein ◽  
P21 Activated Kinase

Activation of the mitotic checkpoint by chemotherapeutic drugs such as taxol causes mammalian cells to arrest in mitosis and then undergo apoptosis. However, the biochemical basis of chemotherapeutic drug-induced cell death is unclear. Herein, we provide new evidence that both cell survival and cell death-signaling pathways are concomitantly activated during mitotic arrest by microtubule-interfering drugs. Treatment of HeLa cells with chemotherapeutic drugs activated both p38 mitogen-activated protein kinase (MAPK) and p21-activated kinase (PAK). p38 MAPK was necessary for chemotherapeutic drug-induced cell death because the p38 MAPK inhibitors SB203580 or SB202190 suppressed cell death. Dominant-active MKK6, a direct activator of p38 MAPK, also induced cell death by stimulating translocation of Bax from the cytosol to the mitochondria in a p38 MAPK-dependent manner. Dominant active PAK suppressed this MKK6-induced cell death. PAK seems to mediate cell survival by phosphorylating Bad, and inhibition of PAK in mitotically arrested cells reduced Bad phosphorylation and increased apoptosis. Our results suggest that therapeutic strategies that suppress PAK-mediated survival signals may improve the efficacy of current cancer chemotherapies by enhancing p38 MAPK-mediated cell death.

scholarly journals Native and Polyubiquitinated Forms of Dihydroceramide Desaturase Are Differentially Linked to Human Embryonic Kidney Cell Survival

2018 ◽  
Vol 38 (23) ◽  
Author(s):  
Mariam Alsanafi ◽  
Samuel L. Kelly ◽  
Karawan Jubair ◽  
Melissa McNaughton ◽  
Rothwelle J. Tate ◽  
...  
Keyword(s):  
Cell Survival ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Sphingosine Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Dihydroceramide Desaturase ◽  
Sphingosine Kinase Inhibitor ◽  
Dependent Mechanism

ABSTRACT There is controversy concerning the role of dihydroceramide desaturase (Degs1) in regulating cell survival, with studies showing that it can both promote and protect against apoptosis. We have therefore investigated the molecular basis for these opposing roles of Degs1. Treatment of HEK293T cells with the sphingosine kinase inhibitor SKi [2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole] or fenretinide, but not the Degs1 inhibitor GT11 {N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octan-amide}, induced the polyubiquitination of Degs1 (Mr = 40 to 140 kDa) via a mechanism involving oxidative stress, p38 mitogen-activated protein kinase (MAPK), and Mdm2 (E3 ligase). The polyubiquitinated forms of Degs1 exhibit “gain of function” and activate prosurvival pathways, p38 MAPK, c-Jun N-terminal kinase (JNK), and X-box protein 1s (XBP-1s). In contrast, another sphingosine kinase inhibitor, ABC294640 [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide], at concentrations of 25 to 50 μM failed to induce formation of the polyubiquitinated forms of Degs1. In contrast to SKi, ABC294640 (25 μM) promotes apoptosis of HEK293T cells via a Degs1-dependent mechanism that is associated with increased de novo synthesis of ceramide. These findings are the first to demonstrate that the polyubiquitination of Degs1 appears to change its function from proapoptotic to prosurvival. Thus, polyubiquitination of Degs1 might provide an explanation for the reported opposing functions of this enzyme in cell survival/apoptosis.

scholarly journals B-Raf Inhibits Programmed Cell Death Downstream of Cytochrome c Release from Mitochondria by Activating the MEK/Erk Pathway

1999 ◽  
Vol 19 (8) ◽  
pp. 5308-5315 ◽  
Author(s):  
Peter Erhardt ◽  
Erin J. Schremser ◽  
Geoffrey M. Cooper
Keyword(s):  
Growth Factor ◽  
Cell Survival ◽  
Fibroblast Cell ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Erk Pathway ◽  
Caspase Activation ◽  
Cytochrome C Release ◽  
Growth Factor Deprivation ◽  
Mitogen Activated Protein

ABSTRACT Growth factor-dependent kinases, such as phosphatidylinositol 3-kinase (PI 3-kinase) and Raf kinases, have been implicated in the suppression of apoptosis. We have recently established Rat-1 fibroblast cell lines overexpressing B-Raf, leading to activation of the MEK/Erk mitogen-activated protein kinase pathway. Overexpression of B-Raf confers resistance to apoptosis induced by growth factor withdrawal or PI 3-kinase inhibition. This is accompanied by constitutive activation of Erk without effects on the PI 3-kinase/Akt pathway. The activity of MEK is essential for cell survival mediated by B-Raf overexpression, since either treatment with the specific MEK inhibitor PD98059 or expression of a dominant inhibitory MEK mutant blocks the antiapoptotic activity of B-Raf. Activation of MEK is not only necessary but also sufficient for cell survival because overexpression of constitutively activated MEK, Ras, or Raf-1, like B-Raf, prevents apoptosis after growth factor deprivation. Overexpression of B-Raf did not interfere with the release of cytochrome c from mitochondria after growth factor deprivation. However, the addition of cytochrome c to cytosols of cells overexpressing B-Raf failed to induce caspase activation. It thus appears that the B-Raf/MEK/Erk pathway confers protection against apoptosis at the level of cytosolic caspase activation, downstream of the release of cytochromec from mitochondria.

scholarly journals N-Methyl-N-Nitrosourea-Induced Photoreceptor Degeneration Is Inhibited by Nicotinamide via the Blockade of Upstream Events before the Phosphorylation of Signalling Proteins

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Eriko Sugano ◽  
Kitako Tabata ◽  
Tsubasa Takezawa ◽  
Raki Shiraiwa ◽  
Hiroki Muraoka ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Molecular Mechanisms ◽  
Camp Response Element Binding ◽  
Mitogen Activated Protein Kinase ◽  
Photoreceptor Degeneration ◽  
Creb Phosphorylation ◽  
Photoreceptor Layer ◽  
Mitogen Activated Protein ◽  
Element Binding Protein

N-methyl-N-nitrosourea (MNU), a known carcinogen, is generally used in animal models to chemically induce photoreceptor degeneration. It has been reported that nicotinamide (NAM) exerts a protective effect on MNU-induced photoreceptor degeneration. We investigated the molecular mechanisms on MNU-induced photoreceptor degeneration. Intraperitoneal MNU injection (75 mg/kg) in rats induced selective photoreceptor degeneration in 7 days. NAM administration completely inhibited photoreceptor degeneration. Photoreceptor layer abnormality was observed within 6 hours after MNU injection, whereas it was restored in the NAM-treated retina, as detected by optical coherence tomography. One day following MNU administration, phosphorylation of the cell death-associated signalling proteins c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) increased, while the apoptosis-related proteins, full-length poly(ADP-ribose) polymerase (PARP) and apoptosis-inducing factor (AIF), were depleted. These changes were not observed in the NAM-treated retinas. Cell survival signalling, such as extracellular signal-regulated kinase (ERK), Akt, and cAMP response element binding protein (CREB) phosphorylation, increased in the MNU- but not in the NAM-treated rat retinas. Increased phosphorylated ERK (p-ERK) levels were observed within 6 hours after MNU administration, suggestive of cell survival signalling activation. This did not occur in NAM-treated retinas. These results indicate that NAM regulates upstream cellular events prior to the activation of cell death-related signalling events, such as JNK and p38 phosphorylation.

Adaptive concentrations of hydrogen peroxide suppress cell death by blocking the activation of SAPK/JNK pathway

2001 ◽  
Vol 114 (23) ◽  
pp. 4329-4334
Author(s):  
Do Kyun Kim ◽  
Eun Sook Cho ◽  
Je Kyung Seong ◽  
Hong-Duck Um
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Adaptive Response ◽  
Time Lag ◽  
Mitogen Activated Protein Kinase ◽  
Cross Resistance ◽  
Jnk Pathway ◽  
Serum Withdrawal ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Low levels of H2O2 can induce cellular resistance to subsequent higher levels of H2O2. By using human U937 leukemia cells, it was previously shown that such an adaptive response can be induced without increasing the cellular capacity to degrade H2O2, thus conferring on the cells a cross-resistance to other stimuli such as serum withdrawal and C2-ceramide. In this study, it was found that stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) acts as a common mediator of the cell death induced by high H2O2 concentrations, serum withdrawal and C2-ceramide. Although SAPK/JNK activation by H2O2 was mediated by two upstream mitogen-activated protein kinase (MAPK) kinases MKK4 and MKK7, only MKK7 played such a role in serum withdrawal and C2-ceramide. Interestingly, all these lethal stimuli failed to activate SAPK/JNK and its upstream kinases in the cells that were pretreated with low adaptive concentrations of H2O2. By contrast, the phosphorylation levels of extracellular signal-regulated kinase and p38 MAPK were not significantly influenced by this H2O2 pretreatment. Inducing the SAPK/JNK-suppressing effect of H2O2 required a time lag, which correlated with the time lag required for the induction of the adaptive response. Overall, the results suggest that H2O2 adaptation confers on cells a resistance to multiple stimuli by specifically blocking their ability to activate the SAPK/JNK pathways.

scholarly journals Lysophosphatidic acid prevents apoptosis in fibroblasts via Gi-protein-mediated activation of mitogen-activated protein kinase

2000 ◽  
Vol 352 (1) ◽  
pp. 135-143 ◽  
Author(s):  
Xianjun FANG ◽  
Shuangxing YU ◽  
Ruth LAPUSHIN ◽  
Yiling LU ◽  
Tatsuro FURUI ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Survival ◽  
Lysophosphatidic Acid ◽  
Protein S ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Proliferative Effect ◽  
Mitogen Activated Protein ◽  
Gi Protein ◽  
Induced Apoptosis

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid with multiple biological functions. In the present study, we demonstrate that, besides its mitogenic activity, LPA is a potent survival factor, preventing serum-deprivation-induced apoptosis in fibroblasts and other cell types. Both the proliferative effect and survival activity of LPA are sensitive to the action of pertussis toxin (PTX), indicating that both processes are mediated by Gi protein(s). We therefore focused on the role of Gi-protein-mediated signalling events in the promotion of cell survival by LPA. In addition to activation of mitogen-activated protein kinase (MAPK), LPA stimulates a modest PTX-sensitive phosphorylation/activation of the serine/threonine kinase Akt, a survival mediator downstream of phosphoinositide 3-kinase (PI3K). Inhibition of PI3K with LY 294002 or wortmannin resulted in a marked inhibition of LPA-induced DNA synthesis, and yet the survival activity of LPA decreased by only 20–30%, suggesting a limited input of the PI3K–Akt cascade in LPA-induced cell survival. In contrast, inhibition of MAPK activation by the MEK-1 inhibitor, PD 98059, blocked both the proliferative and survival effects of LPA. These results indicate that LPA promotes cell survival largely via Gi-protein-mediated activation of ERK1/ERK2, or other PD 98059-sensitive member(s) of the MAPK family.

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