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 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 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 Phosphorylation of androgen receptor isoforms

2004 ◽  
Vol 383 (2) ◽  
pp. 267-276 ◽  
Author(s):  
Hao Yun WONG ◽  
Jan A. BURGHOORN ◽  
Marije van LEEUWEN ◽  
Petra E. de RUITER ◽  
Esther SCHIPPERS ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
De Novo ◽  
Major Change ◽  
Reversed Phase ◽  
Mitogen Activated Protein Kinase ◽  
Reversed Phase Hplc ◽  
De Novo Synthesis ◽  
Elution Pattern ◽  
Receptor Isoforms ◽  
Mitogen Activated Protein

Phosphorylation of the human AR (androgen receptor) is directly correlated with the appearance of at least three AR isoforms on an SDS/polyacrylamide gel. However, it is still not clear to what extent phosphorylation is involved in the occurrence of isoforms, which sites are phosphorylated and what are the functions of these phosphosites. The human AR was expressed in COS-1 cells and AR phosphorylation was studied further by mutational analyses and by using reversed-phase HPLC and MS. The reversed-phase HPLC elution pattern of the three isoforms revealed that Ser-650 was phosphorylated constitutively. After de novo synthesis, only Ser-650 was phosphorylated in the smallest isoform of 110 kDa and both Ser-650 and Ser-94 were phosphorylated in the second isoform of 112 kDa. The hormone-induced 114 kDa isoform shows an overall increase in phosphorylation of all the isolated peptides. The activities of the Ser–Ala substitution mutant S650A (Ser-650→Ala) was found to be identical with wild-type AR activation in four different cell lines and three different functional analyses, e.g. transactivation, N- and C-terminal-domain interaction and co-activation by transcriptional intermediary factor 2. This was also found for mutants S94A and S515A with respect to transactivation. However, the S515A mutation, which should eliminate phosphorylation of the potential mitogen-activated protein kinase site, Ser-515, resulted in an unphosphorylated form of the peptide containing Ser-650. This suggests that Ser-515 can modulate phosphorylation at another site. The present study shows that the AR isoform pattern from AR de novo synthesis is directly linked to differential phosphorylation of a distinct set of sites. After mutagenesis of these sites, no major change in functional activity of the AR was observed.

Review of treatment and therapeutic targets in brain arteriovenous malformation

2021 ◽  
pp. 0271678X2110267
Author(s):  
Peipei Pan ◽  
Shantel Weinsheimer ◽  
Daniel Cooke ◽  
Ethan Winkler ◽  
Adib Abla ◽  
...  
Keyword(s):  
Animal Models ◽  
De Novo ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Current Treatment ◽  
Mitogen Activated Protein Kinase ◽  
De Novo Mutations ◽  
Genetic Syndromes ◽  
Mitogen Activated Protein

Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase ( MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.

scholarly journals Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase

2007 ◽  
Vol 405 (3) ◽  
pp. 617-623 ◽  
Author(s):  
Emma V. Jones ◽  
Mark J. Dickman ◽  
Alan J. Whitmarsh
Keyword(s):  
Dna Damage ◽  
Stress Responses ◽  
Tumour Progression ◽  
Chemotherapeutic Agents ◽  
Signalling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
P53 Family ◽  
Jnk Pathway ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis

The JNK (c-Jun N-terminal kinase)/mitogen-activated protein kinase signalling pathway is a major mediator of stress responses in cells, including the response to DNA damage. DNA damage also causes the stabilization and activation of p73, a member of the p53 family of transcription factors. p73, like p53, can mediate apoptosis by up-regulating the expression of pro-apoptotic genes, including Bax (Bcl2-associated X protein) and PUMA (p53 up-regulated modulator of apoptosis). Changes in p73 expression have been linked to tumour progression, particularly in neuroblastomas, whereas in tumours that feature inactivated p53 there is evidence that p73 may mediate the apoptotic response to chemotherapeutic agents. In the present study, we demonstrate a novel link between the JNK signalling pathway and p73. We use pharmacological and genetic approaches to show that JNK is required for p73-mediated apoptosis induced by the DNA damaging agent cisplatin. JNK forms a complex with p73 and phosphorylates it at several serine and threonine residues. The mutation of JNK phosphorylation sites in p73 abrogates cisplatin-induced stabilization of p73 protein, leading to a reduction in p73 transcriptional activity and reduced p73-mediated apoptosis. Our results demonstrate that the JNK pathway is an important regulator of DNA damage-induced apoptosis mediated by p73.

scholarly journals Pro-apoptotic and pro-proliferation functions of the JNK pathway of Drosophila : roles in cell competition, tumorigenesis and regeneration

Open Biology ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 180256 ◽  
Author(s):  
Noelia Pinal ◽  
Manuel Calleja ◽  
Ginés Morata
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Animal Species ◽  
Mitogen Activated Protein Kinase ◽  
Intrinsic Properties ◽  
Cell Competition ◽  
Apparent Paradox ◽  
Jnk Pathway ◽  
Mitogen Activated Protein ◽  
Cellular Context

The Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family. It appears to be conserved in all animal species where it regulates important physiological functions involved in apoptosis, cell migration, cell proliferation and regeneration. In this review, we focus on the functions of JNK in Drosophila imaginal discs, where it has been reported that it can induce both cell death and cell proliferation. We discuss this apparent paradox in the light of recent findings and propose that the pro-apoptotic and the pro-proliferative functions are intrinsic properties of JNK activity. Whether one function or another is predominant depends on the cellular context.

Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature

2006 ◽  
Vol 291 (2) ◽  
pp. H517-H531 ◽  
Author(s):  
Anuradha Dhanasekaran ◽  
Rula Al-Saghir ◽  
Bernardo Lopez ◽  
Daling Zhu ◽  
David D. Gutterman ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Survival ◽  
Kinase Inhibitor ◽  
Protective Action ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Epoxyeicosatrienoic Acids ◽  
Protective Effects ◽  
Human Coronary Artery ◽  
Mitogen Activated Protein

Epoxyeicosatrienoic acids (EETs) are cytochrome P-450 (CYP) metabolites synthesized from the essential fatty acid arachidonic acid to generate four regioisomers, 14,15-, 11,12-, 8,9-, and 5,6-EET. Cultured human coronary artery endothelial cells (HCAECs) contain endogenous EETs that are increased by stimulation with physiological agonists such as bradykinin. Because EETs are known to modulate a number of vascular functions, including angiogenesis, we tested each of the four regioisomers to characterize their effects on survival and apoptosis of HCAECs and cultured human lung microvascular endothelial cells (HLMVECs). A single application of physiologically relevant concentration of 14,15-, 11,12-, and 8,9-EET but not 5,6-EET (0.75–300 nM) promoted concentration-dependent increase in cell survival of HLMVECs and HCAECs after removal of serum. The lipids also protected the same cells from death via the intrinsic, as well as extrinsic, pathways of apoptosis. EETs did not increase intracellular calcium concentration ([Ca2+]i) or phosphorylate mitogen-activated protein kinase p44/42 when applied to these cells, and their protective action was attenuated by the phosphotidylinositol-3 kinase inhibitor wortmannin (10 μM) but not the cyclooxygenase inhibitor indomethacin (20 μM). Our results demonstrate for the first time the capacity of EETs to enhance human endothelial cell survival by inhibiting both the intrinsic, as well as extrinsic, pathways of apoptosis, an important underlying mechanism that may promote angiogenesis and endothelial survival during atherosclerosis and related cardiovascular ailments.

Sign in / Sign up

Export Citation Format

Share Document