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Wim J. Blitterswijk - One of the best experts on this subject based on the ideXlab platform.

  • diacylglycerol generated by exogenous phospholipase c activates the mitogen activated protein kinase pathway independent of ras and phorbol ester sensitive protein kinase c dependence on protein kinase c zeta
    Biochemical Journal, 1997
    Co-Authors: M C M Van Dijk, Francisco J G Muriana, P C J Van Der Hoeven, Wouter H Moolenaar, Dick Schaap, John Widt, Wim J. Blitterswijk
    Abstract:

    The role of diacylglycerol (DG) formation from phosphatidylcholine in Mitogenic Signal transduction is poorly understood. We have generated this lipid at the plasma membrane by treating Rat-1 fibroblasts with bacterial phosphatidylcholine-specific phospholipase C (PC-PLC). This treatment leads to activation of mitogen-activated protein kinase (MAPK). However, unlike platelet-derived growth factor (PDGF) or epidermal growth factor (EGF), PC-PLC fails to activate Ras and to induce DNA synthesis, and activates MAPK only transiently ( in vitro , using biotinylated e-peptide as a substrate. Furthermore, dominant-negative PKC-ζ inhibits, while (wild-type) PKC-ζ overexpression enhances MAPK activation by PDGF and PC-PLC. The results suggest that DG generated by PC-PLC can activate the MAPK pathway independent of Ras and phorbol-ester-sensitive PKC but, instead, via PKC-ζ.

  • diacylglycerol generated by exogenous phospholipase c activates the mitogen activated protein kinase pathway independent of ras and phorbol ester sensitive protein kinase c dependence on protein kinase c zeta
    Biochemical Journal, 1997
    Co-Authors: M C M Van Dijk, Francisco J G Muriana, P C J Van Der Hoeven, Wouter H Moolenaar, Dick Schaap, John Widt, Wim J. Blitterswijk
    Abstract:

    The role of diacylglycerol (DG) formation from phosphatidylcholine in Mitogenic Signal transduction is poorly understood. We have generated this lipid at the plasma membrane by treating Rat-1 fibroblasts with bacterial phosphatidylcholine-specific phospholipase C (PC-PLC). This treatment leads to activation of mitogen-activated protein kinase (MAPK). However, unlike platelet-derived growth factor (PDGF) or epidermal growth factor (EGF), PC-PLC fails to activate Ras and to induce DNA synthesis, and activates MAPK only transiently ( in vitro , using biotinylated e-peptide as a substrate. Furthermore, dominant-negative PKC-ζ inhibits, while (wild-type) PKC-ζ overexpression enhances MAPK activation by PDGF and PC-PLC. The results suggest that DG generated by PC-PLC can activate the MAPK pathway independent of Ras and phorbol-ester-sensitive PKC but, instead, via PKC-ζ.

Sarmila Majumder - One of the best experts on this subject based on the ideXlab platform.

  • Anti-microRNA-222 (Anti-miR-222) and -181B Suppress Growth of Tamoxifen-resistant Xenografts in Mouse by Targeting TIMP3 Protein and Modulating Mitogenic Signal
    The Journal of biological chemistry, 2011
    Co-Authors: Satavisha Roy, Gerard J. Nuovo, Bhuvaneswari Ramaswamy, Tyler E. Miller, Charles L. Shapiro, Samson T. Jacob, Sarmila Majumder
    Abstract:

    We have shown earlier that miR-221 and -222 are up-regulated in tamoxifen-resistant MCF-7 (OHT(R)) cells and Her2-positive human breast tumors when compared with Her2 negative tumors. In this study, we report markedly enhanced expression of miR-181b in OHT(R) cells and endocrine-resistant tumors. Further, anti-miR-222 or -181b in combination with tamoxifen suppressed growth of tamoxifen-resistant xenografts in mice. Luciferase reporter assay and expression analysis showed that TIMP3, a tissue metalloproteinase inhibitor, is a common target of miR-221/222 and -181b. In situ hybridization and immunohistochemical analysis demonstrated reciprocal relationships between TIMP3 and miR-221/222/181b expression in primary human breast carcinomas. Ectopic expression of TIMP3 inhibited growth of the OHT(R) cells, and its depletion in MCF-7 cells reduced sensitivity to tamoxifen in vitro and in vivo. EGF-induced MAPK and AKT phosphorylation were significantly higher in OHT(R) cells and miR-221/222-overexpressing MCF-7 cells than in control cells, which suggests modulation of Mitogenic Signaling by TIMP3 and the miRs. On the contrary, phosphoMAPK and phosphoAKT levels were diminished in TIMP3-overexpressing OHT(R) cells and increased in TIMP3-depleted MCF-7 cells. Low levels of estrogen or tamoxifen elicited similar differences in phosphoMAPK levels in these cells. Reduced levels of TIMP3 facilitated growth of tamoxifen-resistant cells by alleviating its inhibitory effect on ADAM10 and ADAM17, which are critical for OHT(R) cell growth. In conclusion, miR-221/222 and -181b facilitate growth factor Signaling in tamoxifen-resistant breast cancer by down-regulating TIMP3, and corresponding anti-miRs can be used to render these tumors responsive to tamoxifen.

  • anti mir 222 and 181b suppresses growth of tamoxifen resistant xenografts in mouse by targeting timp3 and modulating Mitogenic Signal
    Journal of Biological Chemistry, 2011
    Co-Authors: Satavisha Roy, Gerard J. Nuovo, Bhuvaneswari Ramaswamy, Tyler E. Miller, Charles L. Shapiro, Samson T. Jacob, Sarmila Majumder
    Abstract:

    Abstract We have shown earlier that miR-221 and -222 are upregulated in tamoxifen resistant MCF-7 (OHTR) cells and Her2 positive human breast tumors compared to Her2 negative tumors. In this study, we report markedly enhanced expression of miR-181b in OHTR cells and endocrine resistant tumors. Further, antimiR- 222 or -181b in combination with tamoxifen suppressed growth of tamoxifen resistant xenografts in mice. Luciferase reporter assay and expression analysis showed that TIMP3, a tissue metalloproteinase inhibitor, is a common target of miR-221/222 and 181b. In situ hybridization and immunohistochemical analysis demonstrated reciprocal relationships between TIMP3 and miR-221/222/181b expression in primary human breast carcinomas. Ectopic expression of TIMP3 inhibited growth of the OHTR cells and its depletion in MCF7 cells reduced sensitivity to tamoxifen in vitro and in vivo. EGF-induced MAPK and AKT phosphorylation were significantly higher in OHTR cells and miR- 221/222 overexpressing MCF-7 cells than in control cells, which suggests modulation of Mitogenic Signaling by TIMP3 and the miRs. On the contrary, phosphoMAPK and phosphoAKT levels were diminished in TIMP3 overexpressing OHTR cells and increased in TIMP3 -depleted MCF-7 cells. Low level of estrogen or tamoxifen elicited similar differences in phosphoMAPK levels in these cells. Reduced level of TIMP3 facilitated growth of tamoxifen resistant cells by alleviating its inhibitory effect on ADAM10 and ADAM17 that are critical for OHTR cell growth. In conclusion, miR-221/222 and -181b facilitate growth factor Signaling in tamoxifen resistant breast cancer by downregulating TIMP3, and corresponding antimiRs can be used to render these tumors responsive to tamoxifen.

Weimin Fan - One of the best experts on this subject based on the ideXlab platform.

  • periodic mechanical stress stimulates the fak Mitogenic Signal in rat chondrocytes through erk1 2 activity
    Cellular Physiology and Biochemistry, 2013
    Co-Authors: Wenwei Liang, Kewei Ren, Feng Liu, Weiding Cui, Qing Wang, Zhefeng Chen, Weimin Fan
    Abstract:

    Background/Aims: The biological effects of periodic mechanical stress on chondrocytes have been studied extensively over the past few years. However, the mechanis

  • periodic mechanical stress activates integrinβ1 dependent src dependent plcγ1 independent rac1 Mitogenic Signal in rat chondrocytes through erk1 2
    Cellular Physiology and Biochemistry, 2012
    Co-Authors: Kewei Ren, Feng Liu, Yumin Huang, Wenwei Liang, Weiding Cui, Qing Wang, Weimin Fan
    Abstract:

    The effects of periodic mechanical stress on the mitogenesis of chondrocytes have been studied extensively in recent years. However, the mechanisms underlying the ability of chondrocytes to sense and respond to periodic mechanical stress remain a matter of debate. We explored the Signal transduction pathways of proliferation and matrix synthesis when chondrocytes were exposed to periodic mechanical stress. We observed that periodic mechanical stress statistically and significantly enhanced the phosphorylation and activation of Rac1 (p<0.05 for each). Pre-treatment with the Rac1 selective inhibitor NSC23766 attenuated periodic mechanical stress-induced chondrocyte proliferation and matrix synthesis (p<0.05 for each) and abrogated ERK1/2 Signal activation (p<0.05), but did not block periodic mechanical stressinduced Src and PLCγ1 phosphorylation in this context. In addition, inhibition of Src with its selective inhibitor PP2 and shRNA targeted to Src blocked Rac1 Signal activation (p<0.05 for each), but inhibition of the activity of PLCγ1 did not affect the phosphorylation and activation levels of Rac1 under conditions of periodic mechanical stress. The up-regulation of proliferation and matrix synthesis was inhibited in chondrocytes in response to periodic mechanical stress after pretreatment with blocking antibody against integrinβ1 (p<0.05 for each) but not after pretreatment with blocking antibody against integrinβ3. The phosphorylation levels of ERK1/2, Rac1, PLCγ1 and Src, and Rac1 activation level were also reduced when integrinβ1 was blocked in this context (p<0.05 for each). These findings suggest that periodic mechanical stress promotes chondrocyte proliferation and matrix synthesis in part by activating the ERK1/2 Mitogenic Signal through the integrinβ1-Src-PLCγ1/Rac1-ERK1/2 pathway, which links these important Signaling molecules into Mitogenic cascades.

M C M Van Dijk - One of the best experts on this subject based on the ideXlab platform.

  • diacylglycerol generated by exogenous phospholipase c activates the mitogen activated protein kinase pathway independent of ras and phorbol ester sensitive protein kinase c dependence on protein kinase c zeta
    Biochemical Journal, 1997
    Co-Authors: M C M Van Dijk, Francisco J G Muriana, P C J Van Der Hoeven, Wouter H Moolenaar, Dick Schaap, John Widt, Wim J. Blitterswijk
    Abstract:

    The role of diacylglycerol (DG) formation from phosphatidylcholine in Mitogenic Signal transduction is poorly understood. We have generated this lipid at the plasma membrane by treating Rat-1 fibroblasts with bacterial phosphatidylcholine-specific phospholipase C (PC-PLC). This treatment leads to activation of mitogen-activated protein kinase (MAPK). However, unlike platelet-derived growth factor (PDGF) or epidermal growth factor (EGF), PC-PLC fails to activate Ras and to induce DNA synthesis, and activates MAPK only transiently ( in vitro , using biotinylated e-peptide as a substrate. Furthermore, dominant-negative PKC-ζ inhibits, while (wild-type) PKC-ζ overexpression enhances MAPK activation by PDGF and PC-PLC. The results suggest that DG generated by PC-PLC can activate the MAPK pathway independent of Ras and phorbol-ester-sensitive PKC but, instead, via PKC-ζ.

  • diacylglycerol generated by exogenous phospholipase c activates the mitogen activated protein kinase pathway independent of ras and phorbol ester sensitive protein kinase c dependence on protein kinase c zeta
    Biochemical Journal, 1997
    Co-Authors: M C M Van Dijk, Francisco J G Muriana, P C J Van Der Hoeven, Wouter H Moolenaar, Dick Schaap, John Widt, Wim J. Blitterswijk
    Abstract:

    The role of diacylglycerol (DG) formation from phosphatidylcholine in Mitogenic Signal transduction is poorly understood. We have generated this lipid at the plasma membrane by treating Rat-1 fibroblasts with bacterial phosphatidylcholine-specific phospholipase C (PC-PLC). This treatment leads to activation of mitogen-activated protein kinase (MAPK). However, unlike platelet-derived growth factor (PDGF) or epidermal growth factor (EGF), PC-PLC fails to activate Ras and to induce DNA synthesis, and activates MAPK only transiently ( in vitro , using biotinylated e-peptide as a substrate. Furthermore, dominant-negative PKC-ζ inhibits, while (wild-type) PKC-ζ overexpression enhances MAPK activation by PDGF and PC-PLC. The results suggest that DG generated by PC-PLC can activate the MAPK pathway independent of Ras and phorbol-ester-sensitive PKC but, instead, via PKC-ζ.

Jorge Moscat - One of the best experts on this subject based on the ideXlab platform.

  • phospholipid degradation and ζpkc activation during Mitogenic Signal transduction
    1994
    Co-Authors: Jorge Moscat, Maria T Diazmeco
    Abstract:

    A number of recent studies suggest a role for phospholipid degradation in MitogenicSignaltransduction pathways. Particularly, the phosphodiesterase-mediated hydrolysis of phosphatidylcholine (PC) has been demonstrated in our and other laboratories to be activated in response to growth factors and oncogenes (1,2). In this regard, we have also produced evidence that activation of PLC-catalyzed hydrolysis of phosphatidylcholine (PC-PLC) is an important step in Mitogenic Signalling (2,3). In Xenopus laevis oocytes, microinjection of transforming ras p21 is a potent inducer of maturation, whereas microinjection of a neutralizing anti-ras p21 antibody specifically inhibits maturation induced by insulin but not by progesterone. Results from our laboratory demonstrate that microinjection of phosphatidylcholine-hydrolyzing phospholipase C (PC-PLC) is sufficient to induce maturation of Xenopus laevis oocytes (3).

  • Hydrolysis of phosphatidylcholine couples Ras to activation of Raf protein kinase during Mitogenic Signal transduction.
    Molecular and cellular biology, 1993
    Co-Authors: Hong Cai, Jakob Troppmair, G Sithanandam, Peter Erhardt, Maria T. Diaz-meco, Jorge Moscat, Geoffrey M. Cooper
    Abstract:

    We have investigated the relationship between hydrolysis of phosphatidylcholine (PC) and activation of the Raf-1 protein kinase in Ras-mediated transduction of Mitogenic Signals. As previously reported, cotransfection of a PC-specific phospholipase C (PC-PLC) expression plasmid bypassed the block to cell proliferation resulting from expression of the dominant inhibitory mutant Ras N-17. In contrast, PC-PLC failed to bypass the inhibitory effect of dominant negative Raf mutants, suggesting that PC-PLC functions downstream of Ras but upstream of Raf. Consistent with this hypothesis, treatment of quiescent cells with exogenous PC-PLC induced Raf activation, even when normal Ras function was blocked by Ras N-17 expression. Further, activation of Raf in response to Mitogenic growth factors was blocked by inhibition of endogenous PC-PLC. Taken together, these results indicate that hydrolysis of PC mediates Raf activation in response to Mitogenic growth factors.

  • protein kinase c ζ isoform is critical for Mitogenic Signal transduction
    Cell, 1993
    Co-Authors: Edurne Berra, Maria T Diazmeco, Isabel Dominguez, M M Municio, Laura Sanz, Jose Manuel Lozano, Robert S Chapkin, Jorge Moscat
    Abstract:

    The requirement of protein kinase C zeta (zeta PKC) for maturation of X. laevis oocytes in response to insulin, p21ras, and phosphatidylcholine-hydrolyzing phospholipase C has recently been shown. Here we present experimental evidence demonstrating that activation of zeta PKC is not only necessary but also sufficient by itself to activate maturation in oocytes and to produce deregulation of growth control in mouse fibroblasts. Furthermore, by using a dominant kinase-defective mutant of zeta PKC, we confirm that this kinase is required for Mitogenic activation in oocytes and fibroblasts. These results permit us to propose zeta PKC as a critical step downstream of p21ras in Mitogenic Signal transduction.

  • hydrolysis of phosphatidylcholine is stimulated by ras proteins during Mitogenic Signal transduction
    Molecular and Cellular Biology, 1992
    Co-Authors: Hong Cai, Peter Erhardt, Jorge Moscat, Maria T Diazmeco, Jozsef Szeberenyi, Terje Johansen, Geoffrey M. Cooper
    Abstract:

    Abstract We have used a dominant inhibitory ras mutant (Ha-ras Asn-17) to investigate the relationship of Ras proteins to hydrolysis of phosphatidylcholine (PC) in the transduction of Mitogenic Signals. Expression of Ha-Ras Asn-17 inhibited NIH 3T3 cell proliferation induced by polypeptide growth factors or phorbol esters. In contrast, the Mitogenic activity of PC-specific phospholipase C (PC-PLC) was not inhibited by Ha-Ras Asn-17 expression. Similarly, cotransfection with a cloned PC-PLC gene bypassed the block to NIH 3T3 cell proliferation resulting from expression of the inhibitory ras mutant. Hydrolysis of PC can therefore induce cell proliferation in the absence of normal Ras activity, suggesting that PC-derived second messengers may act downstream of Ras in Mitogenic Signal transduction. This was substantiated by the finding that Ha-Ras Asn-17 expression inhibited growth factor-stimulated hydrolysis of PC. Taken together, these results indicate that PC hydrolysis is a target of Ras during the transduction of growth factor-initiated Mitogenic Signals.

  • evidence for a role of protein kinase c zeta subspecies in maturation of xenopus laevis oocytes
    Molecular and Cellular Biology, 1992
    Co-Authors: Isabel Dominguez, Edurne Berra, Maria T Diazmeco, M M Municio, Laura Sanz, Garcia A De Herreros, M E Cornet, Jorge Moscat
    Abstract:

    A number of studies have demonstrated the activation of phospholipase C-mediated hydrolysis of phosphatidylcholine (PC-PLC) both by growth factors and by the product of the ras oncogene, p21ras. Evidence has been presented indicating that the stimulation of this phospholipid degradative pathway is sufficient to activate mitogenesis in fibroblasts as well as that it is sufficient and necessary for induction of maturation in Xenopus laevis oocytes. However, the mechanism whereby PC-PLC transduces Mitogenic Signals triggered by growth factors or oncogenes remains to be elucidated. In this study, data are presented that show the involvement of protein kinase C zeta subspecies in the channelling of the Mitogenic Signal activated by insulin-p21ras-PC-PLC in Xenopus oocytes as well as the lack of a critical role of protein kinase C isotypes alpha, beta, gamma, delta, and epsilon in these pathways.