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| IJCEM Copyright © 2008-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711 |
Int J Clin Exp Med 2012;5(3):221-228
Original Article
Induced PDK1 kinase activity suppresses apoptosis in intestinal epithelial cells by
activating akt signaling following polyamine depletion
Kaspar M Keledjian, Bernard S Marasa, Jian-Ying Wang, Jaladanki N Rao
Departments of Surgery, Departments of Pathology, University of Maryland School of Medicine, Baltimore Veterans Affairs Medical
Center, Baltimore, Maryland 21201, USA
Received March 5, 2012; accepted May 11, 2012; Epub June 15, 2012; Published June 30, 2012
Abstract: Apoptosis plays a critical role in the maintenance of gut mucosal homeostasis and is highly regulated by numerous factors
including polyamines. Decreasing cellular polyamines promotes the resistance of intestinal epithelial cells (IECs) to apoptosis by
increasing Akt kinase activity, but the exact mechanisms by which polyamine depletion activates Akt remain unknown.
3-phosphoinositide-dependent protein kinase-1 (PDK1), functions as a downstream of phosphatidylinositol-3 kinase (PI3K) and
upstream of Akt and serves as a major regulator of Akt activity. The current study determined if polyamines regulate Akt activity by
altering PDK1. Studies were conducted in IEC-6 cells, derived from rat small intestinal crypts. Depletion of cellular polyamines induced
PDK1 phosphorylation and increased its kinase activity, which were prevented by exogenous polyamine putrescine. Induced PDK1
activation following polyamine depletion was associated with an increase in phosphorylated Akt (pAkt) and Akt kinase activity. In
contrast, polyamine depletion did not alter levels of total PDK1 and Akt proteins. PDK1 silencing in polyamine-deficient cells not only
prevented the induced Akt activation but also blocked the increased resistance to apoptosis. These results indicate that polyamine
depletion enhanced Akt phosphorylation by increasing PDK1 kinase activity, thereby protecting IECs against apoptosis.
(IJCEM1203003)
Keywords: Intestinal epithelium, Akt phosphorylation, apoptosis, siRNA, polyamines
Address all correspondence to:
Dr. Jaladanki N Rao
Department of Surgery
University of Maryland School of Medicine
and Baltimore Veterans Affairs Medical Center
10 North Greene Street, Baltimore, MD 21201, USA.
Tel: 410-605-7808; Fax: 410-605-7949
E-mail: jrao@umaryland.edu
Original Article
Induced PDK1 kinase activity suppresses apoptosis in intestinal epithelial cells by
activating akt signaling following polyamine depletion
Kaspar M Keledjian, Bernard S Marasa, Jian-Ying Wang, Jaladanki N Rao
Departments of Surgery, Departments of Pathology, University of Maryland School of Medicine, Baltimore Veterans Affairs Medical
Center, Baltimore, Maryland 21201, USA
Received March 5, 2012; accepted May 11, 2012; Epub June 15, 2012; Published June 30, 2012
Abstract: Apoptosis plays a critical role in the maintenance of gut mucosal homeostasis and is highly regulated by numerous factors
including polyamines. Decreasing cellular polyamines promotes the resistance of intestinal epithelial cells (IECs) to apoptosis by
increasing Akt kinase activity, but the exact mechanisms by which polyamine depletion activates Akt remain unknown.
3-phosphoinositide-dependent protein kinase-1 (PDK1), functions as a downstream of phosphatidylinositol-3 kinase (PI3K) and
upstream of Akt and serves as a major regulator of Akt activity. The current study determined if polyamines regulate Akt activity by
altering PDK1. Studies were conducted in IEC-6 cells, derived from rat small intestinal crypts. Depletion of cellular polyamines induced
PDK1 phosphorylation and increased its kinase activity, which were prevented by exogenous polyamine putrescine. Induced PDK1
activation following polyamine depletion was associated with an increase in phosphorylated Akt (pAkt) and Akt kinase activity. In
contrast, polyamine depletion did not alter levels of total PDK1 and Akt proteins. PDK1 silencing in polyamine-deficient cells not only
prevented the induced Akt activation but also blocked the increased resistance to apoptosis. These results indicate that polyamine
depletion enhanced Akt phosphorylation by increasing PDK1 kinase activity, thereby protecting IECs against apoptosis.
(IJCEM1203003)
Keywords: Intestinal epithelium, Akt phosphorylation, apoptosis, siRNA, polyamines
Address all correspondence to:
Dr. Jaladanki N Rao
Department of Surgery
University of Maryland School of Medicine
and Baltimore Veterans Affairs Medical Center
10 North Greene Street, Baltimore, MD 21201, USA.
Tel: 410-605-7808; Fax: 410-605-7949
E-mail: jrao@umaryland.edu
