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Am J Physiol Cell Physiol 296: C801-C810, 2009. First published January 28, 2009; doi:10.1152/ajpcell.00620.2008
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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Polyamines regulate E-cadherin transcription through c-Myc modulating intestinal epithelial barrier function

Lan Liu,1,3 Xin Guo,1,3 Jaladanki N. Rao,1,3 Tongtong Zou,1,3 Lan Xiao,1,3 Tingxi Yu,1,3 Jennifer A. Timmons,1,3 Douglas J. Turner,1,3 and Jian-Ying Wang1,2,3

1Cell Biology Group, Department of Surgery, 2Department of Pathology, University of Maryland School of Medicine, Baltimore; and 3Baltimore Veterans Affairs Medical Center, Baltimore, Maryland

Submitted 2 December 2008 ; accepted in final form 21 January 2009

The integrity of the intestinal epithelial barrier depends on intercellular junctions that are highly regulated by numerous extracellular and intracellular factors. E-cadherin is found primarily at the adherens junctions in the intestinal mucosa and mediates strong cell-cell contacts that have a functional role in forming and regulating the epithelial barrier. Polyamines are necessary for E-cadherin expression, but the exact mechanism underlying polyamines remains elusive. The current study was performed to determine whether polyamines induce E-cadherin expression through the transcription factor c-Myc and whether polyamine-regulated E-cadherin plays a role in maintenance of the epithelial barrier integrity. Decreasing cellular polyamines reduced c-Myc and repressed E-cadherin transcription as indicated by a decrease in levels of E-cadherin promoter activity and its mRNA. Forced expression of the c-myc gene by infection with adenoviral vector containing c-Myc cDNA stimulated E-cadherin promoter activity and increased E-cadherin mRNA and protein levels in polyamine-deficient cells. Experiments using different E-cadherin promoter mutants revealed that induction of E-cadherin transcription by c-Myc was mediated through the E-Pal box located at the proximal region of the E-cadherin promoter. Decreased levels of E-cadherin in polyamine-deficient cells marginally increased basal levels of paracellular permeability but, remarkably, potentiated H2O2-induced epithelial barrier dysfunction. E-cadherin silencing by transfection with its specific small interfering RNA also increased vulnerability of the epithelial barrier to H2O2. These results indicate that polyamines enhance E-cadherin transcription by activating c-Myc, thus promoting function of the epithelial barrier.

paracellular permeability; adherens junctions; gene expression; ornithine decarboxylase; intestinal epithelial cells


Address for reprint requests and other correspondence: J.-Y. Wang, Baltimore Veterans Affairs Medical Center (112), 10 North Greene St., Baltimore, MD 21201 (e-mail:jwang{at}smail.umaryland.edu)






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