Activation of TGF- -Smad signaling pathway following polyamine depletion in intestinal epithelial cells
نویسندگان
چکیده
Liu, Lan, Rachel Santora, Jaladanki N. Rao, Xin Guo, Tongtong Zou, Huifang M. Zhang, Douglas J. Turner, and Jian-Ying Wang. Activation of TGF-Smad signaling pathway following polyamine depletion in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 285: G1056–G1067, 2003. First published July 10, 2003; 10.1152/ajpgi.00151.2003.—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/TGFreceptors. The current study went further to determine the possibility that Smads are the downstream intracellular effectors of activated TGF/TGFreceptor 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 sequencespecific 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 DFMOtreated cells prevented the increased Smad transcription activation. Polyamine-deficient cells highly expressed TGFand were growth-arrested at the G1 phase. Inhibition of TGFby treatment with either immunoneutralizing antiTGFantibody or TGFantisense 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/TGFreceptor signaling following polyamine depletion activates Smads, thus resulting in the stimulation of Smad target gene expression.
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