scholarly journals Neuroprotection by Peptide Growth Factors against Anoxia and Nitric Oxide Toxicity Requires Modulation of Protein Kinase C

1995 ◽  
Vol 15 (3) ◽  
pp. 440-449 ◽  
Author(s):  
Kenneth Maiese ◽  
Lauraine Boccone
Keyword(s):  
Nitric Oxide ◽  
Signal Transduction ◽  
Protein Kinase C ◽  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Neuronal Degeneration ◽  
Kinase C ◽  
Peptide Growth Factors ◽  
Pkc Activation

Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) are neuroprotective during anoxia and nitric oxide (NO) toxicity. Signal transduction systems that modulate protein kinase C (PKC) also can modulate the toxic effects of anoxia and NO. We therefore examined whether PKC was involved in the protective effects of bFGF and EGF during anoxia and NO toxicity. Down-regulation or inhibition of PKC activity before anoxia or NO exposure prevented hippocampal neuronal degeneration. Yet, this protective effect of inhibition of PKC activity was not present with the coadministration of growth factors. Combined inhibition of PKC activity and application of bFGF or EGF lessened the protective mechanisms of the growth factors. In addition, the protective ability of the growth factors was lost during anoxia and NO exposure with the activation of PKC, suggesting that at least a minimal degree of PKC activation is necessary for growth factor protection. Although modulation of PKC activity may be a necessary prerequisite for protection against anoxia and NO toxicity by bFGF and EGF, only inhibition of PKC activity, rather than application of the growth factors, was protective following exposure to NO. These results suggest that the mechanism of protection by bFGF and EGF during anoxia and NO toxicity appears initially to be dependent on a minimum degree of PKC activation, but that other signal transduction pathways independent of PKC also may mediate protection by peptide growth factors.

scholarly journals Mitogenic signaling pathways of growth factors can be distinguished by the involvement of pertussis toxin-sensitive guanosine triphosphate-binding protein and of protein kinase C.

1990 ◽  
Vol 1 (10) ◽  
pp. 747-761 ◽  
Author(s):  
N Nishizawa ◽  
Y Okano ◽  
Y Chatani ◽  
F Amano ◽  
E Tanaka ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Protein Kinase C ◽  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Dna Synthesis ◽  
Signaling Pathways ◽  
Pertussis Toxin ◽  
Guanosine Triphosphate ◽  
Kinase C

We have examined the possible involvements of pertussis toxin (PT)-sensitive guanosine triphosphate (GTP)-binding protein (Gp) and protein kinase C (PKC) in the mitogenic signaling pathways of various growth factors by the use of PT-pretreated and/or 12-O-tetradecanoyl phorbol-13-acetate (TPA)-pretreated mouse fibroblasts. Effects of PT pretreatment (inactivation of PT-sensitive Gp) and TPA pretreatment (depletion of PKC) on mitogen-induced DNA synthesis varied significantly and systematically in response to growth factors: mitogenic responses of cells to thrombin, bombesin, and bradykinin were almost completely abolished both in PT- and TPA-pretreated cells; responses to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and vanadate were reduced to approximately 50% both in PT- and TPA-pretreated cells compared with native cells; response to basic fibroblast growth factor (bFGF) was not affected in PT-pretreated cells but was inhibited to some extent in TPA-pretreated cells. Thus, growth factors examined have been classified into three groups with regard to the involvements of PT-sensitive Gp and PKC in their signal transduction pathways. Binding of each growth factor to its receptor was not affected significantly by pretreatment of cells with PT or TPA. Inhibitory effects of PT and TPA pretreatment on each mitogen-induced DNA synthesis were not additive, suggesting that the functions of PT-sensitive Gp and PKC lie on an identical signal transduction pathway. Although all three groups of mitogens activated PKC, signaling of each growth factor depends to a varying extent on the function of PKC. Our results indicate that a single peptide growth factor such as EGF, PDGF, or bFGF acts through multiple signaling pathways to induce cell proliferation.

Mechanism of sodium transport inhibition by epidermal growth factor in cortical collecting ducts

1991 ◽  
Vol 261 (5) ◽  
pp. F896-F903 ◽  
Author(s):  
V. M. Vehaskari ◽  
J. Herndon ◽  
L. L. Hamm
Keyword(s):  
Signal Transduction ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Na Transport ◽  
Kinase C ◽  
Transport Inhibition ◽  
Collecting Ducts ◽  
Epidermal Growth

Epidermal growth factor (EGF) inhibits Na transport in the cortical collecting ducts (CCD). To gain insight into the signal transduction of this effect, several potential mechanisms were examined in rabbit CCD perfused in vitro. Pretreatment with pertussis toxin, indomethacin, or the protein kinase C inhibitor H7 did not prevent the acute 34-50% decrease in lumen-to-bath 22Na flux (JNa) on exposure to peritubular EGF, indicating that the inhibition is not mediated by a Gi protein, prostaglandin E2 (PGE2), or protein kinase C. Inhibition of the basolateral Na-H exchanger was also without an effect. Lowering the bath Ca concentration from 1.2 to 0.11 mM did not prevent the inhibition of JNa by EGF (JNa decreased significantly by 38.7 +/- 6.9% and 29.1 +/- 5.3%, respectively); in contrast, reduction of the bath free Ca to 0.005 mM totally abolished the effect of EGF. The response to EGF was also assessed in the setting of chronic stimulation of Na transport; inhibition of JNa by EGF was still observed in CCD from remnant kidneys and in CCD from mineralocorticoid-treated rabbits. The results demonstrate that the inhibition of CCD Na transport by EGF is dependent on peritubular Ca. This suggests that the signal transduction involves Ca influx across the basolateral membrane and that increased cytosolic free Ca may be a common pathway for the counterregulatory control of Na reabsorption by several agonists.

scholarly journals Regulation of epidermal-growth-factor-receptor signal transduction by cis-unsaturated fatty acids. Evidence for a protein kinase C-independent mechanism

1991 ◽  
Vol 278 (3) ◽  
pp. 679-687 ◽  
Author(s):  
X Casabiell ◽  
A Pandiella ◽  
F F Casanueva
Keyword(s):  
Signal Transduction ◽  
Fatty Acids ◽  
Protein Kinase C ◽  
Oleic Acid ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Cell Lines ◽  
Kinase C ◽  
Epidermal Growth

The effect of acute treatment with non-esterified fatty acids (NEFA) on transmembrane signalling has been investigated in three different cell lines. In EGFR T17 cells, pretreatment with cis-unsaturated (oleic and palmitoleic acids) NEFA, but not with saturated or trans-unsaturated NEFA, inhibited the epidermal-growth-factor (EGF)-induced increases in cytosolic [Ca2+], membrane potential and Ins(1,4,5)P3 generation. The blocking effect was found to be time- and dose-dependent and rapidly reversible after washout. However, oleic acid treatment did not block either binding of 125I-EGF to its receptor or EGF-induced autophosphorylation of the EGF receptor. The mechanism of action of NEFA could not be attributed to protein kinase C activation, since (i) down-regulation of the enzyme by long-term treatment with phorbol esters did not prevent blockade by oleic acid, and (ii) the effects of acutely administered phorbol ester and oleic acid were additive. In this cell line, signalling at bradykinin and bombesin receptors was also impaired by oleic acid. In A431 cells, oleic acid also blocked signal transduction at the EGF and B2 bradykinin receptors. Finally, in PC12 cells, oleic acid blocked the Ca2+ influx mediated by the activation of B2 bradykinin receptors. In conclusion: (1) NEFA block signal transduction by interfering with receptor-phospholipase C or phospholipase C-substrate interaction without preventing ligand binding; (2) NEFA do not act by a protein kinase C-mediated mechanism; (3) the effect of NEFA is dependent on their configuration rather than hydrophobicity or chain length; (4) this effect is evident in several different cell lines and receptor systems.

Cross-talk between receptors with intrinsic tyrosine kinase activity and α1b-adrenoceptors

2000 ◽  
Vol 350 (2) ◽  
pp. 413-419 ◽  
Author(s):  
Luz DEL CARMEN MEDINA ◽  
José VÁZQUEZ-PRADO ◽  
J. Adolfo GARCÍA-SÁINZ
Keyword(s):  
Protein Kinase C ◽  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Functional Coupling ◽  
Kinase C ◽  
Epidermal Growth ◽  
Phosphoinositide 3 Kinase ◽  
And Function

The effect of epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) on the phosphorylation and function of α1b-adrenoceptors transfected into Rat-1 fibroblasts was studied. EGF and PDGF increased the phosphorylation of these adrenoceptors. The effect of EGF was blocked by tyrphostin AG1478 and that of PDGF was blocked by tyrphostin AG1296, inhibitors of the intrinsic tyrosine kinase activities of the receptors for these growth factors. Wortmannin, an inhibitor of phosphoinositide 3-kinase, blocked the α1b-adrenoceptor phosphorylation induced by EGF but not that induced by PDGF. Inhibition of protein kinase C blocked the adrenoceptor phosphorylation induced by EGF and PDGF. The ability of noradrenaline to increase [35S]guanosine 5´-[γ-thio]triphosphate ([35S]GTP[S]) binding in membrane preparations was used as an index of the functional coupling of the α1b-adrenoceptors and G-proteins. Noradrenaline-stimulated [35S]GTP[S] binding was markedly decreased in membranes from cells pretreated with EGF or PDGF. Our data indicate that: (i) activation of EGF and PDGF receptors induces phosphorylation of α1b-adrenoceptors, (ii) phosphatidylinositol 3-kinase is involved in the EGF response, but does not seem to play a major role in the action of PDGF, (iii) protein kinase C mediates this action of both growth factors and (iv) the phosphorylation of α1b-adrenoceptors induced by EGF and PDGF is associated with adrenoceptor desensitization.

scholarly journals Divergent regulation by growth factors and cytokines of 95 kDa and 72 kDa gelatinases and tissue inhibitors or metalloproteinases-1, -2, and -3 in rabbit aortic smooth muscle cells

1996 ◽  
Vol 315 (1) ◽  
pp. 335-342 ◽  
Author(s):  
Rosalind P. FABUNMI ◽  
Andrew H. BAKER ◽  
Edward J. MURRAY ◽  
Robert F. G. BOOTH ◽  
Andrew C. NEWBY
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Basement Membrane ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Tissue Inhibitors ◽  
Kinase C

The migration and proliferation of vascular smooth muscle cells (SMCs) during neointima formation in atherosclerosis and angioplasty restenosis is mediated by certain growth factors and cytokines, one action of which may be to promote basement-membrane degradation. To test this hypothesis further, the effects of such growth factors and cytokines on the synthesis of two basement-membrane-degrading metalloproteinases, namely the 72 kDa gelatinase (MMP-2, gelatinase A) and the 95 kDa gelatinase (MMP-9, gelatinase B) and three tissue inhibitors of metalloproteinases (TIMPs) was studied in primary cultured rabbit aortic SMCs. Expression of the 95 kDa gelatinase was increased by phorbol myristate acetate, foetal calf serum, thrombin and interleukin-1α (IL-1α); platelet-derived growth factor (PDGF) BB alone had no effect but acted synergistically with IL-1α. A selective protein kinase C inhibitor, Ro 31-8220, abolished induction of the 95 kDa gelatinase. In contrast, none of the agents tested modulated the synthesis of the 72 kDa gelatinase. We conclude that maximal up-regulation of 95 kDa gelatinase expression requires the concerted action of growth factors and inflammatory cytokines mediated, in part, by a protein kinase C-dependent pathway. TIMP-1 and TIMP-2 were highly expressed, and their synthesis was not affected by growth factors or cytokines. Expression of TIMP-3 mRNAs was, however, increased by PDGF and transforming growth factor β, especially in combination. Divergent regulation of gelatinase and TIMP expression implies that either net synthesis or net degradation of basement membrane can be mediated by appropriate combinations of growth factors and cytokines.

Effect of a dominant inhibitory Ha-ras mutation on mitogenic signal transduction in NIH 3T3 cells

1990 ◽  
Vol 10 (10) ◽  
pp. 5314-5323
Author(s):  
H Cai ◽  
J Szeberényi ◽  
G M Cooper
Keyword(s):  
Signal Transduction ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Dna Synthesis ◽  
3T3 Cells ◽  
Kinase C ◽  
Mitogenic Signal Transduction ◽  
Nih 3T3 ◽  
Mitogenic Signal

We used a dominant inhibitory mutation of c-Ha-ras which changes Ser-17 to Asn-17 in the gene product p21 [p21(Asn-17)Ha-ras] to investigate ras function in mitogenic signal transduction. An NIH 3T3 cell line [NIH(M17)] was isolated that displayed inducible expression of the mutant Ha-ras gene (Ha-ras Asn-17) via the mouse mammary tumor virus long terminal repeat and was growth inhibited by dexamethasone. The effect of dexamethasone induction on response of quiescent NIH(M17) cells to mitogens was then analyzed. Stimulation of DNA synthesis by epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) was completely blocked by p21(Asn-17) expression, and stimulation by serum, fibroblast growth factor, and platelet-derived growth factor was partially inhibited. However, the induction of fos, jun, and myc by EGF and TPA was not significantly inhibited in this cell line. An effect of p21(Asn-17) on fos induction was, however, demonstrated in transient expression assays in which quiescent NIH 3T3 cells were cotransfected with a fos-cat receptor plasmid plus a Ha-ras Asn-17 expression vector. In this assay, p21(Asn-17) inhibited chloramphenicol acetyltransferase expression induced by EGF and other growth factors. In contrast to its effect on DNA synthesis, however, Ha-ras Asn-17 expression did not inhibit fos-cat expression induced by TPA. Conversely, downregulation of protein kinase C did not inhibit fos-cat induction by activated ras or other oncogenes. These results suggest that ras proteins are involved in at least two parallel mitogenic signal transduction pathways, one of which is independent of protein kinase C. Although either pathway alone appears to be sufficient to induce fos, both appear to be necessary to induce the full mitogenic response.

scholarly journals Regulation of pp90rsk phosphorylation and S6 phosphotransferase activity in Swiss 3T3 cells by growth factor-, phorbol ester-, and cyclic AMP-mediated signal transduction.

1991 ◽  
Vol 11 (4) ◽  
pp. 1861-1867 ◽  
Author(s):  
R H Chen ◽  
J Chung ◽  
J Blenis
Keyword(s):  
Signal Transduction ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Phorbol Ester ◽  
Kinase Activity ◽  
Sodium Vanadate ◽  
S6 Kinase ◽  
Kinase C

Somatic cell homologs to the Xenopus laevis S6 protein kinases (referred to collectively as pp90rsk) have recently been identified and partially characterized. Here we examine alterations in pp90rsk phosphorylation and S6 phosphotransferase activity in response to regulators of multiple signal transduction systems: purified growth factors, phorbol ester, changes in cyclic AMP (cAMP) levels, and sodium vanadate. All reagents tested increased pp90rsk serine and threonine phosphorylation, but only those agents that regulate cell proliferation and sodium vanadate activated its S6 kinase activity. In addition to the cAMP-stimulated phosphorylation of pp90rsk, a simple correlation between the extent of growth-regulated pp90rsk phosphorylation and S6 phosphotransferase activity was not observed. Quantitative phosphorylation of pp90rsk continued to increase after its S6 kinase activity began its return towards basal levels. However, a close correlation between the appearance and disappearance of a slow-mobility form of phosphorylated pp90rsk (by electrophoresis) and pp90rsk activity was observed. In addition, pp90rsk was regulated by both protein kinase C-independent and -dependent signaling mechanisms. The extent of protein kinase C participation, however, varied depending on which growth factor receptor was activated. Furthermore, growth factor-specific differences in the temporal regulation of pp90rsk S6 phosphotransferase activity were also observed. These results support the notion that the complex regulation of the rsk gene product constitutes one of the primary responses of animal cells to mitogenic signals.

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