RGD Reference Report - Activation of TGF-beta-Smad signaling pathway following polyamine depletion in intestinal epithelial cells. - Rat Genome Database

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

Authors: Liu, L  Santora, R  Rao, JN  Guo, X  Zou, T  Zhang, HM  Turner, DJ  Wang, JY 
Citation: Liu L, etal., Am J Physiol Gastrointest Liver Physiol 2003 Nov;285(5):G1056-67. Epub 2003 Jul 10.
RGD ID: 1304404
Pubmed: PMID:12855402   (View Abstract at PubMed)
DOI: DOI:10.1152/ajpgi.00151.2003   (Journal Full-text)

Smad proteins are transcription activators that are critical for transmitting transforming growth factor-beta (TGF-beta) 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-beta/TGF-beta receptors. The current study went further to determine the possibility that Smads are the downstream intracellular effectors of activated TGF-beta/TGF-beta receptor signaling following polyamine depletion. Studies were conducted in IEC-6 cells derived from rat small intestinal crypts. Depletion of cellular polyamines by alpha-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-beta and were growth-arrested at the G1 phase. Inhibition of TGF-beta by treatment with either immunoneutralizing anti-TGF-beta antibody or TGF-beta 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-beta/TGF-beta receptor signaling following polyamine depletion activates Smads, thus resulting in the stimulation of Smad target gene expression.

Objects referenced in this article
Gene Smad3 SMAD family member 3 Rattus norvegicus
Gene Smad4 SMAD family member 4 Rattus norvegicus

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