Transformation by H-ras can result in aberrant regulation of ornithine decarboxylase gene expression by transforming growth factor-beta(1)

Inhibition of DNA synthesis and cell proliferation is frequently lost durin g malignant transformation and occasionally, tumour cell proliferation is a ctually stimulated by transforming growth factor beta (1) (TGF-beta (1)). T he present study demonstrates a novel link between alterations in TGF-beta (1) regulation during cellular transformation and malignant conversion and the expression of ornithine decarboxylase (ODC) which is a key rate limitin g activity in the biosynthesis of polyamines and which is an enzyme that pl ays an important role in cell growth and differentiation. H-ras transformed mouse 10T1/2 cell lines of varying degrees of malignant potential were exa mined for possible TGF-beta (1)-mediated alterations in ODC expression. Sel ective induction of ODC gene expression occurred. This induction was depend ent upon the cellular phenotype expressed and the mechanisms responsible fo r the regulation of the TGF-beta (1)-mediated alterations in ODC expression varied as a function of malignant potential. The TGF-beta (1)-mediated alt erations in ODC gene expression involves de novo protein synthesis, transcr iptional, and post-transcriptional events. Evidence is also presented to su ggest a possible role for protein kinase C-mediated events, protein phospha tases, and G-protein-coupled events in the TGF-beta (1) mediated regulation of ODC expression in H-ras transformed cells. Evidence is also presented t o suggest a possible role for cellular polyamines in the TGF-beta (1)-media ted alterations in ODC expression in H-ras transformed cells. Additionally, alterations in cellular polyamines were shown to influence TGF-beta (1) ge ne expression in H-ras transformed cells and that these alterations occurre d, in part, through post-transcriptional events. The TGF-beta (1)-mediated regulation of ODC expression in H-ras transformed cells of varying degrees of malignant potential appears to be complex, multifaceted, and interactive . This study illustrates the importance of TGF-beta (1)-mediated regulation of ODC expression as a result of H-ras mediated cellular transformation an d malignant progression, and further suggests that this TGF-beta (1)-mediat ed regulation constitutes an integral part of an altered growth regulatory program. (C) 2001 Wiley-Liss, Inc.