title: Expression of the TGF-beta receptor gene and sensitivity to growth inhibition following polyamine depletion.
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-beta (TGF-beta). This study went further to determine whether expression of the TGF-beta 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 alpha-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-beta type I receptor (TGF-betaRI) mRNA and protein but had no effect on the TGF-beta type II receptor expression. The induced TGF-betaRI expression after polyamine depletion was associated with an increased sensitivity to growth inhibition induced by exogenous TGF-beta but not by somatostatin. Extracellular matrix laminin inhibited IEC-6 cell growth without affecting the TGF-beta receptor expression. Laminin consistently failed to induce the sensitivity of TGF-beta-mediated growth inhibition. In addition, decreasing TGF-betaRI expression by treatment with retinoic acid not only decreased TGF-beta-mediated growth inhibition in normal cells but also prevented the increased sensitivity to exogenous TGF-beta in polyamine-deficient cells. These results indicate that 1) depletion of cellular polyamines by DFMO increases expression of the TGF-betaRI gene and 2) increased TGF-betaRI expression plays an important role in the process through which polyamine depletion sensitizes intestinal epithelial cells to growth inhibition induced by TGF-beta.
authors.affiliation: Department of Surgery, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Rao
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: B L
authors.initials: BL
authors.lastname: Bass
authors.forename: J Y
authors.initials: JY
authors.lastname: Wang
mesh_terms: D030201:Activin Receptors, Type I; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D007797:Laminin / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D011700:Putrescine / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics*; D013095:Spermidine / Q000378:metabolism*; D013096:Spermine / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007797:Laminin; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D013096:Spermine; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625843:Tgfbr1 protein, rat; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine