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

Abstract

Inhibition of DNA synthesis and cell proliferation is frequently lost during malignant transformation and occasionally, tumour cell proliferation is actually stimulated by transforming growth factor beta(1) (TGF-beta(1)). The 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 limiting activity in the biosynthesis of polyamines and which is an enzyme that plays an important role in cell growth and differentiation. H-ras transformed mouse 10T(1/2) cell lines of varying degrees of malignant potential were examined for possible TGF-beta(1)-mediated alterations in ODC expression. Selective induction of ODC gene expression occurred. This induction was dependent upon the cellular phenotype expressed and the mechanisms responsible for the regulation of the TGF-beta(1)-mediated alterations in ODC expression varied as a function of malignant potential. The TGF-beta(1)-mediated alterations in ODC gene expression involves de novo protein synthesis, transcriptional, and post-transcriptional events. Evidence is also presented to suggest a possible role for protein kinase C-mediated events, protein phosphatases, and G-protein-coupled events in the TGF-beta(1)-mediated regulation of ODC expression in H-ras transformed cells. Evidence is also presented to suggest a possible role for cellular polyamines in the TGF-beta(1)-mediated alterations in ODC expression in H-ras transformed cells. Additionally, alterations in cellular polyamines were shown to influence TGF-beta(1) gene expression in H-ras transformed cells and that these alterations occurred, 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 and malignant progression, and further suggests that this TGF-beta(1)-mediated regulation constitutes an integral part of an altered growth regulatory program.

Growth factor‐mediated altered expression and regulation of S‐adenosylmethionine decarboxylase in a H‐ras transformed cell line capable of malignant progression

“…An enhancement of growth rate in response to growth factor treatment would imply that increased SAMDC expression in response to growth factor stimulation is of biological relevance. These observations with SAMDC are also in keeping with studies which indicate that TGF‐beta 1 , bFGF, EGF, and PDGF can all increase the expression of ODC by increasing ODC enzyme activity [Hurta et al, 1993; Hurta et al, 1996; Voskas et al, 1999; Hurta et al, 2001 unpublished observations]. These observations are also consistent with studies, which show a co‐ordinate regulation of both ODC and SAMDC expression in malignant H‐ras transformed cells in response to tumour promoters [Voskas et al, 2001].…”

Polyamines and related signaling pathways in cancer

“…In H-RAS transformed cells, the regulation of multiple cytokines could affect the expression of key enzymes in polyamine anabolism. For example, ODC is regulated by basic fibroblast growth factor (bFGF), transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF), and cAMP [60][61][62][63]. Similarly, S-adenosylmethionine decarboxylase expression is regulated by epidermal growth factor (EGF) and bFGF [64].…”