Expression of the TGF-beta receptor gene and sensitivity to growth inhibition following polyamine depletion |
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Authors: | Rao J N Li L Bass B L Wang J Y |
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Institution: | Department of Surgery, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201, USA. |
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Abstract: | Our previous studieshave shown that inhibition of polyamine biosynthesis increases thesensitivity of intestinal epithelial cells to growth inhibition inducedby exogenous transforming growth factor- (TGF- ). This study wentfurther to determine whether expression of the TGF- receptor genesis involved in this process. Studies were conducted in the IEC-6 cellline, derived from rat small intestinal crypt cells. Administration of -difluoromethylornithine (DFMO), a specific inhibitor of ornithinedecarboxylase (the rate-limiting enzyme for polyamine synthesis), for 4 and 6 days depleted cellular polyamines putrescine, spermidine, andspermine in IEC-6 cells. Polyamine depletion by DFMO increased levelsof the TGF- type I receptor (TGF- RI) mRNA and protein but had noeffect on the TGF- type II receptor expression. The inducedTGF- RI expression after polyamine depletion was associated with anincreased sensitivity to growth inhibition induced by exogenous TGF- but not by somatostatin. Extracellular matrix laminin inhibited IEC-6cell growth without affecting the TGF- receptor expression. Lamininconsistently failed to induce the sensitivity of TGF- -mediatedgrowth inhibition. In addition, decreasing TGF- RI expression bytreatment with retinoic acid not only decreased TGF- -mediated growthinhibition in normal cells but also prevented the increased sensitivityto exogenous TGF- in polyamine-deficient cells. These resultsindicate that 1) depletion of cellular polyamines by DFMOincreases expression of the TGF- RI gene and 2) increasedTGF- RI expression plays an important role in the process throughwhich polyamine depletion sensitizes intestinal epithelial cells togrowth inhibition induced by TGF- . |
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