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

Abstract

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 Ecadherin 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.

Activation of Wnt3a signaling stimulates intestinal epithelial repair by promoting c-Myc-regulated gene expression

“…Our previous studies (24,47) have shown that regenerative gastric and duodenal mucosa after stress is associated with increased expression of the c-Myc gene following increased levels of cellular polyamines and that inhibition of c-Myc expression by polyamine depletion decreases cell renewal and delays mucosal healing. Our results further show that induced c-Myc forms dimers with Max after injury and specifically binds to the DNA sequence in the promoter of its target genes such as p21 and E-cadherin (21,22,23). Because polyamines are necessary but not sufficient for the stimulation of c-Myc expression (22,23), an open question is which cellular signaling or factors initially activate c-Myc gene transcription after GI mucosal injury.…”

“…Our results further show that induced c-Myc forms dimers with Max after injury and specifically binds to the DNA sequence in the promoter of its target genes such as p21 and E-cadherin (21,22,23). Because polyamines are necessary but not sufficient for the stimulation of c-Myc expression (22,23), an open question is which cellular signaling or factors initially activate c-Myc gene transcription after GI mucosal injury.…”

Microtubule disassembly prevents palatal fusion and alters regulation of the E-cadherin/catenin complex

“…We therefore speculated that microtubule disruption affects the positive regulatory pathways that result in the induction of E-cadherin mRNA. c-MYC is one of the down-stream transcription factors regulated by TGF-b and reported to be an E-cadherin transcriptional activator (Batsche et al, 1998, Liu et al, 2009, Pietenpol et al, 1990. We have shown that strong c-MYC signals were maintained even at 48 h in the MEE treated with NDZ, which was associated with its down-stream target ID2 induction.…”

“…E-cadherin transcription is tightly regulated through the promoter that contains a CAAT box, a GC rich region and an E-box. The transcription factor c-MYC transactivates E-cadherin through its direct interaction with the E-box or as a co-activator of AP-2 transcription factor, which interacts with the GC-rich region (Batsche et al, 1998, Liu et al, 2009. TGF-b negatively regulates c-MYC (Pietenpol et al, 1990).…”

L-Arginine Pretreatment Reduces Intestinal Mucositis as Induced by 5-FU in Mice

“…The polyamines from the metabolism of L-arginine or L-ornithine have important roles in the growth, development, and repair of intestinal mucosa (35)(36)(37). The beneficial effects of polyamines on intestinal mucositis (38) and in the regulation of protein expression and members of the tight junctions (39,40) were related. However, further studies are needed.…”