Potentiation of insulin secretion by phorbol esters is mediated by PKC-α and nPKC isoforms

Yaney, Gordon C.; Fairbanks, Jamison M.; Deeney, Jude T.; Korchak, Helen M.; Tornheim, Keith; Corkey, Barbara E.

doi:10.1152/ajpendo.00474.2001

Cited by 33 publications

(45 citation statements)

References 34 publications

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“…It is of interest to note that the present data on PKC down-regulation in BRIN-BD11 cells stand in contrast to those of Yaney et al (2002) who reported that this isoform was retained in HIT-T15 -cells during long-term PMA treatment. The reasons for this difference are unclear but may relate to the finding that, unlike other isoforms of PKC, PKC requires PMA-induced hyperphosphorylation for down-regulation (Srivastava et al 2002).…”

Section: Discussioncontrasting

confidence: 99%

Evidence that protein kinase Cdelta is not required for palmitate-induced cytotoxicity in BRIN-BD11 beta-cells

Welters

Smith²,

Tadayyon³

et al. 2004

Journal of Molecular Endocrinology

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Chronic exposure of pancreatic -cells to saturated fatty acids leads to loss of viability, an effect that has been implicated in the process of -cell 'lipotoxicity' associated with the progression of type 2 diabetes. The mechanisms involved are unknown but recent evidence has implicated the isoform of protein kinase C (PKC ) in mediating fatty acid toxicity. We have investigated this proposition in the clonal insulin-secreting cell line, BRIN-BD11. BRIN-BD11 cells were found to undergo apoptosis when exposed to palmitate and this response was attenuated by the purportedly selective inhibitor of PKC , rottlerin. However, activation of PKC with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), failed to promote cell death and down-regulation of PKC did not prevent the cytotoxic effects of palmitate. Moreover, rottlerin remained effective as a blocker of the palmitate response in cells depleted of PKC . Since rottlerin can inhibit various other kinases in addition to PKC , a range of additional kinase inhibitors was also tested. Of these, only the putative Ca 2+ /calmodulin-dependent protein kinase II (CaM kinase II) inhibitor, KN-62, was found to inhibit palmitate-induced cell death. However, this effect was not reproduced by a more selective pseudo-substrate inhibitor of CaM kinase II. Therefore, the present results reveal that palmitate induces cell death in BRIN-BD11 cells and suggest that this may involve the activation of a rottlerin (and KN-62)-sensitive kinase. However, it is clear that PKC is not required for this response.

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Section: Discussioncontrasting

confidence: 99%

Evidence that protein kinase Cdelta is not required for palmitate-induced cytotoxicity in BRIN-BD11 beta-cells

Welters

Smith²,

Tadayyon³

et al. 2004

Journal of Molecular Endocrinology

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“…In line with this result is a report showing the blocking of NEFA-stimulated secretion by inhibitors of cPKC and nPKC isoforms in perifused rat islets [147]. In addition, we have shown that KCl-induced insulin secretion was also enhanced after PMA downregulation [140,146]). This would suggest that an increased sensitivity of exocytosis to Ca 2+ and/or an increase in the ready releasable pool of secretory granules was due to an increased vesicle priming or to the prior inhibition of exocytosis.…”

Section: Modulation Of Protein Kinase C Isoforms In the Beta Cellsupporting

confidence: 89%

“…Glucose causes a rise in DAG [24,30,142] and promotes the translocation of PKC-α in the beta cell [143,144,145]. This is consistent with the observation that the mass of PKC-α correlates with the ability of phorbol myristate acetate (PMA), a high affinity surrogate for DAG, to stimulate secretion [146]. Therefore, the short-term activation of PKC is thought to be a positive signal for insulin secretion as seen by the effects of either phorbol esters or cell permeant diacylglycerols.…”

Section: Modulation Of Protein Kinase C Isoforms In the Beta Cellsupporting

confidence: 68%

Fatty acid metabolism and insulin secretion in pancreatic beta cells

2003

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Increases in glucose or fatty acids affect metabolism via changes in long-chain acyl-CoA formation and chronically elevated fatty acids increase total cellular CoA. Understanding the response of pancreatic beta cells to increased amounts of fuel and the role that altered insulin secretion plays in the development and maintenance of obesity and Type 2 diabetes is important. Data indicate that the activated form of fatty acids acts as an effector molecule in stimulus-secretion coupling. Glucose increases cytosolic long-chain acylCoA because it increases the "switch" compound malonyl-CoA that blocks mitochondrial β-oxidation, thus implementing a shift from fatty acid to glucose oxidation. We present arguments in support of the following: (i) A source of fatty acid either exogenous or endogenous (derived by lipolysis of triglyceride) is necessary to support normal insulin secretion; (ii) a rapid increase of fatty acids potentiates glucose-stimulated secretion by increasing fatty acyl-CoA or complex lipid concentrations that act distally by modulating key enzymes such as protein kinase C or the exocytotic machinery; (iii) a chronic increase of fatty acids enhances basal secretion by the same mechanism, but promotes obesity and a diminished response to stimulatory glucose; (iv) agents which raise cAMP act as incretins, at least in part, by stimulating lipolysis via beta-cell hormone-sensitive lipase activation. Furthermore, increased triglyceride stores can give higher rates of lipolysis and thus influence both basal and stimulated insulin secretion. These points highlight the important roles of NEFA, LC-CoA, and their esterified derivatives in affecting insulin secretion in both normal and pathological states. [Diabetologia (2003[Diabetologia ( ) 46:1297[Diabetologia ( -1312

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“…Prolonged stimulation with phorbol esters results in down-regulation of some PKC isoforms (Yaney et al, 2002). When BEAS-2B cells were pre-incubated with PMA (50 ng/ml) for 18 h and then stimulated with PMA, MMP-9 induction was significantly reduced (Figure 2A).…”

Section: Pma Induces Mmp-9 Expression In Beas-2b Cellsmentioning

confidence: 99%

PMA-induced up-regulation of MMP-9 is regulated by a PKCα-NF-κB cascade in human lung epithelial cells

Shin

Yoon²,

Choe³

et al. 2007

Exp Mol Med

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Expression of matrix metalloproteinase-9 (MMP-9) is associated with airway remodeling and tissue injury in asthma. However, little is known about how MMP-9 is up-regulated in airway epithelial cells. In this study, we show that phorbol myristate acetate (PMA) induces MMP-9 expression via a protein kinase Cα (PKCα)-dependent signaling cascade in BEAS-2B human lung epithelial cells. Pretreatment with either GF109203X, a general PKC inhibitor, or Gö6976, a PKCα/β isozyme inhibitor, inhibited PMA-induced activation of the MMP-9 promoter, as did transient transfection with PKCα antisense oligonuclotides. PMA activated NF-κB by phosphorylating IκB in these cells and this was also inhibited by GF109203X and Gö6976, suggesting that PKCα acts as an upstream regulator of NF-κB in PMA-induced MMP-9 induction. Our results indicate that a "PKCα-NF-κB"-dependent cascade is involved in the signaling leading to PMA-induced MMP-9 expression in the lung epithelium.

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Potentiation of insulin secretion by phorbol esters is mediated by PKC-α and nPKC isoforms

Cited by 33 publications

References 34 publications

Evidence that protein kinase Cdelta is not required for palmitate-induced cytotoxicity in BRIN-BD11 beta-cells

Evidence that protein kinase Cdelta is not required for palmitate-induced cytotoxicity in BRIN-BD11 beta-cells

Fatty acid metabolism and insulin secretion in pancreatic beta cells

PMA-induced up-regulation of MMP-9 is regulated by a PKCα-NF-κB cascade in human lung epithelial cells

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