Title

Expression of the TGF-β receptor gene and sensitivity to growth inhibition following polyamine depletion

Document Type

Journal Article

Publication Date

1-1-2000

Journal

American Journal of Physiology - Cell Physiology

Volume

279

Issue

4 48-4

DOI

10.1152/ajpcell.2000.279.4.c1034

Keywords

Cell proliferation; IEC-6; Laminin; Retinoic acid; Transforming growth factor-β receptor

Abstract

Our previous studies have shown that inhibition of polyamine biosynthesis increases the sensitivity of intestinal epithelial cells to growth inhibition induced by exogenous transforming growth factor-β (TGF-β). This study went further to determine whether expression of the TGF-β receptor genes is involved in this process. Studies were conducted in the IEC-6 cell line, derived from rat small intestinal crypt cells. Administration of α-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase (the rate-limiting enzyme for polyamine synthesis), for 4 and 6 days depleted cellular polyamines putrescine, spermidine, and spermine in IEC-6 cells. Polyamine depletion by DFMO increased levels of the TGF-β type I receptor (TGF-βRI) mRNA and protein but had no effect on the TGF-β type II receptor expression. The induced TGF-βRI expression after polyamine depletion was associated with an increased sensitivity to growth inhibition induced by exogenous TGF-β but not by somatostatin. Extracellular matrix laminin inhibited IEC-6 cell growth without affecting the TGF-β receptor expression. Laminin consistently failed to induce the sensitivity of TGF-β-mediated growth inhibition. In addition, decreasing TGF-βRI expression by treatment with retinoic acid not only decreased TGF-β-mediated growth inhibition in normal cells but also prevented the increased sensitivity to exogenous TGF-β in polyamine-deficient cells. These results indicate that 1) depletion of cellular polyamines by DFMO increases expression of the TGF-βRI gene and 2) increased TGF-βRI expression plays an important role in the process through which polyamine depletion sensitizes intestinal epithelial cells to growth inhibition induced by TGF-β.

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