Raf-1 kinase inhibitory protein (RKIP) mediates ethanol-induced sensitization of secretagogue signaling in pancreatic acinar cells

Sung Ok Kim, Kirk L. Ives, Xiaofu Wang, Robert A. Davey, Celia Chao, Mark Hellmich

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Excessive alcohol consumption is associated with most cases of chronic pancreatitis, a progressive necrotizing inflammatory disease that can result in pancreatic insufficiency due to acinar atrophy and fibrosis and an increased risk of pancreatic cancer. At a cellular level acute alcohol exposure can sensitize pancreatic acinar cells to secretagogue stimulation, resulting in dysregulation of intracellular Ca2+ homeostasis and premature digestive enzyme activation; however, the molecular mechanisms by which ethanol exerts these toxic effects have remained undefined. In this study we identify Raf-1 kinase inhibitory protein as an essential mediator of ethanol-induced sensitization of cholecystokinin- and carbachol-regulated Ca2+ signaling in pancreatic acinar cells. We show that exposure of rodent acinar cells to ethanol induces protein kinase C-dependent Raf-1 kinase inhibitory protein phosphorylation, sensitization of cholecystokinin-stimulated Ca 2+ signaling, and potentiation of both basal and cholecystokinin- stimulated extracellular signal-regulated kinase activation. Furthermore, we show that either suppression of Raf-1 kinase inhibitory protein expression using short hairpin RNA or gene ablation prevented the sensitizing effects of ethanol on cholecystokinin- and carbachol-stimulated Ca2+ signaling and intracellular chymotrypsin activation in pancreatic acinar cells, suggesting that the modulation of Raf-1 inhibitory protein expression may have future therapeutic utility in the prevention or treatment of alcohol-associated pancreatitis.

Original languageEnglish (US)
Pages (from-to)33377-33388
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number40
DOIs
StatePublished - Sep 28 2012

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Proto-Oncogene Proteins c-raf
Acinar Cells
Cholecystokinin
Ethanol
Chemical activation
Alcohols
Carbachol
Proteins
Exocrine Pancreatic Insufficiency
Phosphorylation
Enzyme Activation
Poisons
Extracellular Signal-Regulated MAP Kinases
Chronic Pancreatitis
Chymotrypsin
Ablation
Pancreatic Neoplasms
Alcohol Drinking
Pancreatitis
Protein Kinase C

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Raf-1 kinase inhibitory protein (RKIP) mediates ethanol-induced sensitization of secretagogue signaling in pancreatic acinar cells. / Kim, Sung Ok; Ives, Kirk L.; Wang, Xiaofu; Davey, Robert A.; Chao, Celia; Hellmich, Mark.

In: Journal of Biological Chemistry, Vol. 287, No. 40, 28.09.2012, p. 33377-33388.

Research output: Contribution to journalArticle

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