The Pivotal Role of Phosphoinositide-3 Kinase in the Human Somatostatin sst4 Receptor-Mediated Stimulation of p44/p42 Mitogen-Activated Protein Kinase and Extracellular Acidification

Smalley, Keiran S.M.; Feniuk, W.; Sellers, Lynda A.; Humphrey, P. P. A.

doi:10.1006/bbrc.1999.1351

Cited by 35 publications

(22 citation statements)

References 21 publications

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“…SB203580 and SB202190, however, failed to inhibit the phosphorylation of Akt (Kim et al, 2003b), indicating that the inhibitory effect of SB203580 or SB202190 on the insulinmediated increase in mEH protein expression is not due to inhibition of PDK1 or its downstream effectors in primary cultured hepatocytes under the conditions employed. A number of studies have reported that the phosphorylation of MAPKs, through activation of a variety of receptors, is regulated by PI3K (Assefa et al, 1999;Sasaoka et al, 1999;Smalley et al, 1999;Hirasawa et al, 2000). The PI3K inhibitors, however, failed to inhibit insulininduced phosphorylation of p38 MAPK (Kim et al, 2003b), in our studies in primary cultured hepatocytes, suggesting that p38 MAPK may represent a distinct pathway responsible for the induction of mEH in response to insulin treatment.…”

Section: Phase II Enzymescontrasting

confidence: 70%

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Kim

Novak

2007

Pharmacology & Therapeutics

142

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Endogenous factors, including hormones, growth factors and cytokines, play an important role in the regulation of hepatic drug metabolizing enzyme expression in both physiological and pathophysiological conditions. Alterations of hepatic drug metabolizing enzymes gene and protein expression, observed in diabetes, fasting, obesity, protein-calorie malnutrition and long-term alcohol consumption alters the metabolism of xenobiotics, including procarcinogens, carcinogens, toxicants, and therapeutic agents and may also impact the efficacy and safety of therapeutic agents, as well as result in drug-drug interactions. Although the mechanisms by which xenobiotics regulate drug metabolizing enzymes have been studied intensively, less is known regarding the cellular signaling pathways and components which regulate drug metabolizing enzyme gene and protein expression in response to hormones and cytokines. Recent findings, however, have revealed that several cellular signaling pathways are involved in hormone-and growth factor-mediated regulation of drug metabolizing enzymes. Our laboratory, and others, have demonstrated that insulin and growth factors regulate drug metabolizing enzyme gene and protein expression, including cytochromes P450, glutathione S-transferases and microsomal epoxide hydrolase, through receptors which are members of the large receptor tyrosine kinase family, and by downstream effectors such as phosphatidylinositol 3-kinase, the mitogen activated protein kinase, Akt/protein kinase B, mTOR, and the p70S6 kinase. Here, we review current knowledge of the signaling pathways implicated in regulation of drug metabolizing enzyme gene and protein expression in response to insulin and growth factors, with the goal of increasing our understanding of how chronic disease affects these signaling pathways, components, and ultimately gene expression and translational control.

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Section: Phase II Enzymescontrasting

confidence: 70%

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Kim

Novak

2007

Pharmacology & Therapeutics

142

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“…To determine the possible role of MAP kinases in mediating TSA-induced histone H3 phosphorylation at serine 28 in vivo, we first examined the influence of specific chemical inhibitors of MEK1 and p38 kinase on TSA-induced H3 phosphorylation at serine 28 in JB6 PD98059 is a specific inhibitor of the activation of MEK1 (Alessi et al, 1995;Oh-hashi et al, 1999;Smalley et al, 1999). We have reported previously that PD98059 inhibits UV-induced phosphorylation of ERKs, but has no effect on p38 kinase or JNKs phosphorylation (Zhang et al, 2001a, b;She et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation at serine 28 and acetylation at lysine 9 of histone H3 induced by trichostatin A

et al. 2003

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Trichostatin A (TSA), a histone deacetylase inhibitor, strongly increases acetylation of the N-terminal tails of histone H3. Many studies have correlated the function of TSA with the hyperacetylation of histone. Although histone H3 is known to be phosphorylated, the effect of acetylation on phosphorylation is not known. Here, we report that in JB6 cells, TSA induces both acetylation at lysine 9 and phosphorylation at serine 28 of histone H3. UVB irradiation, which is known to induce phosphorylation at serine 28, did not significantly affect phosphorylation of histone H3 in TSA-pretreated JB6 cells. In contrast, TSA markedly increased phosphorylation and acetylation of histone H3 in UVB-pretreated JB6 cells. TSA strongly activated MAP kinases. Moreover, PD98059 and SB202190 inhibited TSA-induced phosphorylation but not acetylation of histone H3. Dominant negative mutant ERK2 and dominant negative mutant p38 kinase blocked TSA-stimulated phosphorylation of histone H3 at serine 28. The results indicate that TSAinduced phosphorylation of histone H3 at serine 28 occurs through activation of the MAP kinase pathway and phosphorylated histone H3 is more sensitive to TSAinduced hyperacetylation. The facilitation of phosphorylation and acetylation of histone H3 induced by TSA may play a critical regulatory role in chromatin remodeling and gene expression.

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“…However, there are possibly also other types of desensitization that affect components downstream of the receptors; examples include agonist-induced phosphorylation of G-proteins, phospholipase C, and adenylyl cyclase (Clark et al, 1999). Smalley et al (1998Smalley et al ( , 2001 have reported that the desensitization of h sst 4 -mediated EAR responses is not likely to involve receptor internalization but seems to take place upstream of mitogen-activated protein kinase (Smalley et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Differential Efficacies of Somatostatin Receptor Agonists for G-Protein Activation and Desensitization of Somatostatin Receptor Subtype 4-Mediated Responses

Engström¹,

Savola²,

Wurster³

2005

J Pharmacol Exp Ther

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Although desensitization represents an important physiological feedback mechanism that protects against overstimulation, it can significantly limit the therapeutic usefulness of drugs. In the current investigation, we have employed Cytosensor microphysiometry for the purpose of determining the propensity of somatostatin receptor agonists to induce desensitization of the human somatostatin receptor subtype 4 (h sst 4 )-mediated extracellular acidification rate (EAR) response in intact Chinese hamster ovary (CHO) cells. We have compared this propensity with the efficacies of the agonists as measured in a , which we also found to be an h sst 4 superagonist, albeit to a lesser degree than J-2156, demonstrated a high propensity to cause desensitization. Our results indicate that there is no relationship between the efficacy of the agonists to cause G-protein activation and their ability to induce desensitization of the h sst 4 -mediated EAR responses. The finding that on the h sst 4 , J-2156 is not only a superagonist but also shows a low propensity to cause desensitization, might offer therapeutic advantages. At a minimum, the compound will be a powerful tool to study the mechanisms connected to efficacy and desensitization of h sst 4 -mediated responses.

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The Pivotal Role of Phosphoinositide-3 Kinase in the Human Somatostatin sst4 Receptor-Mediated Stimulation of p44/p42 Mitogen-Activated Protein Kinase and Extracellular Acidification

Cited by 35 publications

References 21 publications

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Phosphorylation at serine 28 and acetylation at lysine 9 of histone H3 induced by trichostatin A

Differential Efficacies of Somatostatin Receptor Agonists for G-Protein Activation and Desensitization of Somatostatin Receptor Subtype 4-Mediated Responses

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