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MUCOSAL BIOLOGY

Activation of TGF--Smad signaling pathway following polyamine depletion in intestinal epithelial cells

Departments of ¹Surgery and ³Pathology, University of Maryland School of Medicine, and ²Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201

Submitted 1 April 2003 ; accepted in final form 9 July 2003

Smad proteins are transcription activators that are critical for transmitting transforming growth factor- (TGF-) superfamily signals from the cell surface receptors to the nucleus. Our previous studies have shown that cellular polyamines are essential for normal intestinal mucosal growth and that a decreased level of polyamines inhibits intestinal epithelial cell proliferation, at least partially, by increasing expression of TGF-/TGF- receptors. The current study went further to determine the possibility that Smads are the downstream intracellular effectors of activated TGF-/TGF- receptor signaling following polyamine depletion. Studies were conducted in IEC-6 cells derived from rat small intestinal crypts. Depletion of cellular polyamines by -difluoromethylornithine (DFMO) increased basal levels of Smad3 and Smad4 proteins, induced their nuclear translocation, and stimulated Smad sequence-specific DNA-binding activity. Polyamine depletion-induced Smads were also associated with a significant increase in transcription activation as measured by luciferase reporter gene activity of Smad-dependent promoters. Inhibition of Smads by a dominant-negative mutant Smad4 in the DFMO-treated cells prevented the increased Smad transcription activation. Polyamine-deficient cells highly expressed TGF- and were growth-arrested at the G₁ phase. Inhibition of TGF- by treatment with either immunoneutralizing anti-TGF- antibody or TGF- antisense oligodeoxyribonucleotides not only blocked the induction of Smad activity but also decreased the Smad-mediated transcriptional activation in polyamine-depleted cells. These findings suggest that Smads are involved in the downstream cellular processes mediated by cellular polyamines and that increased TGF-/TGF- receptor signaling following polyamine depletion activates Smads, thus resulting in the stimulation of Smad target gene expression.

growth arrest; transforming growth factor- receptor; ornithine decarboxylase; -difluoromethylornithine; crypts

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