Cell Signalling Through Guanine‐Nucleotide‐Binding Regulatory Proteins (G Proteins) and Phospholipases

Exton, John H.

doi:10.1111/j.1432-1033.1997.t01-1-00010.x

Cited by 153 publications

(114 citation statements)

References 117 publications

(85 reference statements)

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“…4). ARF-sensitive PLD activity is located in other cellular membranes [17,271 and it is possible that brefeldin A does not affect the enzyme in these locations. Brefeldin-A-insensitive guaninenucleotide-exchange proteins have been reported for ARF [28,291 and it is possible that these mediate ARF-dependent-agonist activation of PLD in HL-60 cells.…”

Section: Discussionmentioning

confidence: 99%

“…A protein that catalyzes the exchange of guanine nucleotide on ARF has been identified in Golgi preparations and shown to be specifically inhibited by brefeldin A [5, 61. Since ARF binding on Golgi membranes is required for the association of the p-coatamer protein (/I-COP), a component of coatomers, PLD activation by guanosine 5'-[y-thio]triphosphate (GTP [S]) in broken cells is dependent on the small GTP-binding proteins ARF and Rho, and on cytosolic and membrane factors [17]. Although the role of ARF in the regulation of PLD is well established in vitro [13, 14, 171, its involvement in receptormediated PLD regulation in intact cells has been minimally demonstrated [18, 191.…”

Section: Triphosphate (Gtp[s])-dependent Activation Of Phospholipase mentioning

confidence: 99%

“…Changes in membrane lipid composition, resulting from PLD activation, could facilitate the fusion of vesicles enriched with negatively charged phospholipids with acceptor membranes [12, 161. PLD activation by guanosine 5'-[y-thio]triphosphate (GTP [S]) in broken cells is dependent on the small GTP-binding proteins ARF and Rho, and on cytosolic and membrane factors [17]. Although the role of ARF in the regulation of PLD is well established in vitro [13,14,171, its involvement in receptormediated PLD regulation in intact cells has been minimally demonstrated [18,191.…”

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Effects of Brefeldin A on Phosphatidylcholine Phospholipase D and Inositolphospholipid Metabolism in HL‐60 Cells

Guillemain

Exton

1997

European Journal of Biochemistry

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The involvement of the small GTP-binding protein ADP-ribosylation factor (ARF) in guanosine 5'- [y-thio] triphosphate (GTP[S])-dependent activation of phospholipase D (PLD) in HL-60 cells has been well established in vitro.In this study, we tested the effect of brefeldin A, which prevents ARF activation by inhibiting guanine-nucleotide-exchange activity, on PLD stimulation by receptor agonists (formylMet-Leu-Phe and ATP) and by the phorbol ester phorbol 12-myristate 13-acetate (PMA) in differentiated HL-60 cells. However, brefeldin A did not affect the activation of PLD at a time (1 h) when it eliminated the activity of the trans-Golgi enzyme galactosyltransferase. It also did not inhibit PLD activity in Golgienriched membranes treated with GTP[S] with or without ARF in vitro. However, longer times of brefeldin A treatment (> 6 h), progressively and completely inhibited the activation of PLD by formyl-MetLeu-Phe and partly inhibited (~5 0 % ) the activation by PMA. In contrast, long-term brefeldin A treatment did not inhibit the effect of GTP[S] on PLD in permeabilized HL-60 cells. Long-term brefeldin A treatment completely inhibited inositol phosphate production in response to formyl-Met-Leu-Phe and ATP, indicating that it affected inositolphospholipid-specific phospholipase C activity. These data indicate that the rapid inhibitory effect of brefeldin A on Golgi function is not associated with inhibition of receptormediated or PMA-mediated PLD activation in HL-60 cells. However, longer-term effects, presumably arising from the disruption of the Golgi, lead to a total inhibition of agonist activation of PLD and inositolphospholipid-specific phospholipase C. In summary, these results do not support a role for brefeldin-A-sensitive ARF in agonist regulation of PLD in HL-60 cells.Keywords: phospholipase D ; ADP-ribosylation factor; brefeldin A; inositolphospholipid; Golgi.Brefeldin A is a fungal metabolite, initially reported to inhibit protein secretion [l]. It inhibits vesicular transport in the Golgi complex and causes a rapid resorption of most of the Golgi membrane into the endoplasmic reticulum [2] and association of Golgi enzymes with the endoplasmic reticulum, thereby eliminating the Golgi complex as a morphologically distinct organelle [3]. Morphological changes in the Golgi and redistribution of Golgi markers are observed within minutes of addition of brefeldin A. Upon removal of brefeldin A, the morphology of the Golgi is rapidly restored, and normal protein transport and sorting resumes.The earliest detectable event in the action of brefeldin A is prevention of the GTP-dependent interaction with Golgi membranes of ADP-ribosylation factor (ARF), a small GTP-binding protein [4]. A protein that catalyzes the exchange of guanine nucleotide on ARF has been identified in Golgi preparations and shown to be specifically inhibited by brefeldin A [5, 61. Since ARF binding on Golgi membranes is required for the association of the p-coatamer protein (/I-COP), a component of coatomers, PLD activation by guanosine 5...

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Section: Discussionmentioning

confidence: 99%

Section: Triphosphate (Gtp[s])-dependent Activation Of Phospholipase mentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of Brefeldin A on Phosphatidylcholine Phospholipase D and Inositolphospholipid Metabolism in HL‐60 Cells

Guillemain

Exton

1997

European Journal of Biochemistry

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“…The heterotrimeric guanine nucleotide binding regulatory proteins (G-proteins) mediate a variety of cellular processes by coupling transmembrane receptors to d i fferent effector molecules, including adenylyl cyclase and inositol phospholipid-specific phospholipase C (PLC) (Exton, 1997;Eyster, 1998). Activation of Gs/adenylyl cyclase results in the production of cyclic AMP (cAMP) and activation of cAMP-dependent protein kinase (PKA).…”

Section: Introductionmentioning

confidence: 99%

Cholera toxin mediated regulation of the expression of Gqα and G11α GTP binding proteins

Shah

1999

Exp Mol Med

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Previously it has been shown that persistent activation of the stimulatory adenylyl cyclase pathway with cholera toxin (CT) downregulates the Gs polypeptide (80%) in a cAMP-independent manner in C6 glioma cells (Shah, 1997). This study was conducted to examine the short and long term effects of CT on the regulation of pertussis toxin-sensitive andinsensitive G proteins and their transcripts in C6 glioma cells. Treatment of C6 cells with CT (100 ng/ ml) up to 16 h had no effect on either Gi or Gq/11 proteins. However, prolonged exposure (24-48 h) caused increased expression of Gi (20-30%) and G q / 11 proteins (40%). Urea gradient gels, which can separate Gq and G11 proteins, revealed that prolonged CT treatment increased the expression of both of these G proteins. The CT-mediated enhanced expression of Gq and G11 proteins was accompanied by increased mRNA levels of these proteins as determined by RT/PCR. Cyclic-AMP elevating agents like forskolin (10 M) and db-cAMP (1 mM) mimicked the effect of CT on Gi but not Gq/11 proteins. These studies show long term cAMPdependent regulation of Gi and cAMP-independent expression of Gq/11 proteins in C6 glioma cells.

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“…PA is involved in calcium mobilization (Siddiqui and English, 1997), transport from the endoplasmic reticulum to the Golgi complex (Bi et al, 1997) and activation of other signalling cascades (Siddiqui and Yang, 1995;English et al, 1996). PA has been linked to the activation of the neutrophil respiratory burst enzyme, NADPH oxidase (Waite et al, 1997), and is also a potent mitogen, and may exert its effects through the action of the small G-proteins (Exton, 1997). The potential therapeutic index for PA modulators is high, as normal cells under homeostatic conditions have very low levels of PA, malignant transformed cells express high levels of PA.…”

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confidence: 99%

Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours

Cheeseman

Brannan²,

McGown

et al. 2000

Br J Cancer

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Summary CT-2584 HMS, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine-hydrogen methanesulphonate, is a modulator of intracellular phosphatidic acid. We treated 30 patients as part of a Phase I and pharmacokinetic study to determine the maximum-tolerated dose of CT-2584 HMS, toxicity profiles, pharmacokinetic profile and antitumour effects at escalating dose levels. CT-2584 HMS was given as a continuous infusion for 6 hours for 5 consecutive days every 3 weeks. Plasma samples for pharmacokinetic studies were analysed using a validated high-performance liquid chromatographic assay. Mean C max and AUC values for each dose group were similar on days 1 and 5 and increases in plasma concentration (C max and AUC) appeared proportional to the dose. CT-2584 HMS had a mean elimination half-life of 7.3 hours. Values of V d and clearance were independent of dose and duration of treatment. Dose escalation was halted at 585 mg/m 2 because of malaise and lethargy, which was sometimes accompanied by nausea and headache. 26 patients were evaluable for response, one patient with pleural mesothelioma achieved a partial response to treatment confirmed by CT scanning. A dose level of 520 mg/m 2 daily × 5 days would be suitable for Phase II testing. Alternative schedules of CT-2584 HMS to overcome the limiting toxicity of malaise would be worthy of examination.

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Cell Signalling Through Guanine‐Nucleotide‐Binding Regulatory Proteins (G Proteins) and Phospholipases

Cited by 153 publications

References 117 publications

Effects of Brefeldin A on Phosphatidylcholine Phospholipase D and Inositolphospholipid Metabolism in HL‐60 Cells

Effects of Brefeldin A on Phosphatidylcholine Phospholipase D and Inositolphospholipid Metabolism in HL‐60 Cells

Cholera toxin mediated regulation of the expression of Gqα and G11α GTP binding proteins

Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours

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