Diacylglycerols Containing Omega 3 and Omega 6 Fatty Acids Bind to RasGRP and Modulate MAP Kinase Activation

Madani, Sihem; Hichami, Aziz; Charkaoui-Malki, Mustapha; Khan, Naim Akhtar

doi:10.1074/jbc.m306252200

Cited by 43 publications

(27 citation statements)

References 31 publications

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“…Although PKC isozymes and RasGRP possess similar C1 domains, there are differences in their ligand recognition properties (Lorenzo et al, 2000;Shao et al, 2001;Reuther et al, 2002;Rong et al, 2002;Madani et al, 2004;Pu et al, 2005). These differences may be responsible for the distinct dose-response profiles observed for PMA-induced Erk activation in sensitive versus resistant EL4 cells (Ku and Meier, 2000), as well as for the differential effects of various PKC activators on other signaling events in these cells (Sansbury et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells

Han¹,

Knoepp²,

Hallman³

et al. 2006

Mol Pharmacol

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The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to the tumor promoter phorbol 12-myristate 13-acetate (PMA). In sensitive EL4 cells, PMA causes robust Erk mitogen-activated protein kinase activation that results in growth arrest. In resistant cells, PMA induces minimal Erk activation, without growth arrest. PMA stimulates IL-2 production in sensitive, but not resistant, cells. The role of RasGRP1, a PMA-activated guanine nucleotide exchange factor for Ras, in EL4 phenotype was examined. Endogenous RasGRP1 protein is expressed at much higher levels in sensitive than in resistant cells. PMA-induced Ras activation is observed in sensitive cells but not in resistant cells lacking Ras-GRP1. PMA induces down-regulation of RasGRP1 protein in sensitive cells but increases RasGRP1 in resistant cells. Transfection of RasGRP1 into resistant cells enhances PMA-induced Erk activation. In the reverse experiment, introduction of small interfering RNA (siRNA) for RasGRP1 suppresses PMA-induced Ras and Erk activations in sensitive cells. Sensitive cells incubated with siRNA for RasGRP1 exhibit the PMA-resistant phenotype, in that they are able to proliferate in the presence of PMA and do not secrete IL-2 when stimulated with PMA. These studies indicate that the PMA-sensitive phenotype, as previously defined for the EL4 cell line, is conferred by endogenous expression of RasGRP1 protein.EL4, a cell line originated from a carcinogen-induced murine thymoma, provides a unique model system for the study of phorbol ester response and resistance. Responses of sensitive "wild-type" (WT) EL4 cells to phorbol 12-myristate 13-acetate (PMA) include protein kinase C (PKC) activation

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Section: Discussionmentioning

confidence: 99%

RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells

Han¹,

Knoepp²,

Hallman³

et al. 2006

Mol Pharmacol

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“…Moreover, we have demonstrated that DHA inhibits phosphorylation of ERK1/ERK2 (29,34) and proliferation of T-lymphocytes (35) and NIH/3T3 cells (36). Fig.…”

Section: Discussionmentioning

confidence: 99%

Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation

Khan

Nishimura

Aires

et al. 2006

Journal of Lipid Research

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Docosahexaenoic acid (DHA), a PUFA of the n-3 family, inhibited the growth of FM3A mouse mammary cancer cells by arresting their progression from the late-G 1 to the S phase of the cell cycle. DHA upregulated p27Kip1 levels by inhibiting phosphorylation of mitogen-activated protein (MAP) Kip1 contents and inhibited MAPK-dependent proteasomal degradation of this protein. DHA also diminished cyclin E phosphorylation, cyclin-dependent kinase-2 (CDK2) activity, and phosphorylation of retinoblastoma protein in these cells. Our study shows that DHA arrests cell growth by modulating the phosphorylation of cell cycle-related pro-

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“…Although their beneficial effects can no longer be doubted, their molecular mechanisms of action are complex and involve a number of integrated signaling pathways. n-3 PUFAs have been shown to influence lipid microdomains such as lipid rafts and caveolae (Ma et al, 2004), Protein kinase C (PKC) activation (Madani et al, 2001), mitogen-activated protein kinase phosphorylation (Denys et al, 2002(Denys et al, , 2004Madani et al, 2004) and modulation of gene expression (Nakamura et al, 2004). In addition, in vitro studies have demonstrated that EPA and DHA may induce cell death or apoptosis via mitochondrial pathway .…”

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confidence: 99%

Docosahexaenoic Acid Induces Increases in [Ca²⁺]_ivia Inositol 1,4,5-Triphosphate Production and Activates Protein Kinase Cγ and -δ via Phosphatidylserine Binding Site: Implication in Apoptosis in U937 Cells

Aires¹,

Hichami²,

Filomenko³

et al. 2007

Mol Pharmacol

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We investigated, in monocytic leukemia U937 cells, the effects of docosahexaenoic acid (DHA; 22:6 n-3) on calcium signaling and determined the implication of phospholipase C (PLC) and protein kinase C (PKC) in this pathway. DHA induced dose-dependent increases in [Ca 2ϩ ] i , which were contributed by intracellular pool, via the production of inositol-1,4,5-triphosphate (IP 3 ) and storeoperated Ca 2ϩ (SOC) influx, via opening of Ca 2ϩ release-activated Ca 2ϩ (CRAC) channels. Chemical inhibition of PLC, PKC␥, and PKC␦, but not of PKC␤ ⌱/II, PKC␣, or PKC␤I, significantly diminished DHA-induced increases in [Ca 2ϩ ] i . In vitro PKC assays revealed that DHA induced a ϳ2-fold increase in PKC␥ and -␦ activities, which were temporally correlated with the DHA-induced increases in [Ca 2ϩ ] i . In cell-free assays, DHA, but not other structural analogs of fatty acids, activated these PKC isoforms. Competition experiments revealed that DHA-induced activation of both the PKCs was dose-dependently inhibited by phosphatidylserine (PS). Furthermore, DHA induced apoptosis via reactive oxygen species (ROS) production, followed by caspase-3 activation. Chemical inhibition of PKC␥/␦ and of SOC/CRAC channels significantly attenuated both DHA-stimulated ROS production and caspase-3 activity. Our study suggests that DHA-induced activation of PLC/IP 3 pathway and activation of PKC␥/␦, via its action on PS binding site, may be involved in apoptosis in U937 cells.Epidemiological, clinical, and experimental studies have established that ingestion of n-3 polyunsaturated fatty acids (n-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present in marine fish oils, exert beneficial effects in several autoimmune and inflammatory disorders (Calder, 2004) Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.107.039792. ABBREVIATIONS:PUFA, polyunsaturated fatty acid; AA, arachidonic acid; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate; CRAC, Ca 2ϩ release-activated Ca 2ϩ channels; DAG, diacylglycerol; DHA, docosahexaenoic acid; DHA-meth, DHA methyl ester; DHE, dihydroethidine; Dic8, 1,2-dioctanoyl-sn-glycerol; DPEA, cis-7,10,13,16,19-docosapentaenoic acid; DTT, dithiothreitol; EPA, eicosapentaenoic acid; GF 109203X, bisindolylmaleimide I; Gö -6976, 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole; HBDDE, 2,2Ј,3,3Ј,4,4Ј-hexahydroxy-1,1Ј-biphenyl-6,6Ј-dimethanol dimethyl ether; IP 3 , inositol-1,4,5-trisphosphate; LSD, least-significant difference; MBP, myelin basic protein; MMP, mitochondrial membrane potential; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; PS, phosphatidyl-L-serine; ROS, reactive oxygen species; [1][2][3]propoxy]-4-methoxyphenethyl)-1H-imidazole; SOC, store-operated Ca 2ϩ channels; TA9, tyrphostin A9; TG, thapsigargin; U-73122, 1-[6-[[17␤-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]...

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Diacylglycerols Containing Omega 3 and Omega 6 Fatty Acids Bind to RasGRP and Modulate MAP Kinase Activation

Cited by 43 publications

References 31 publications

RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells

RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells

Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation

Docosahexaenoic Acid Induces Increases in [Ca²⁺]_ivia Inositol 1,4,5-Triphosphate Production and Activates Protein Kinase Cγ and -δ via Phosphatidylserine Binding Site: Implication in Apoptosis in U937 Cells

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Diacylglycerols Containing Omega 3 and Omega 6 Fatty Acids Bind to RasGRP and Modulate MAP Kinase Activation

Cited by 43 publications

References 31 publications

RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells

RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells

Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation

Docosahexaenoic Acid Induces Increases in [Ca2+]ivia Inositol 1,4,5-Triphosphate Production and Activates Protein Kinase Cγ and -δ via Phosphatidylserine Binding Site: Implication in Apoptosis in U937 Cells

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Docosahexaenoic Acid Induces Increases in [Ca²⁺]_ivia Inositol 1,4,5-Triphosphate Production and Activates Protein Kinase Cγ and -δ via Phosphatidylserine Binding Site: Implication in Apoptosis in U937 Cells