Opposing effects of mutant ras oncoprotein on human fibroblast and epithelial cell proliferation: implications for models of human tumorigenesis

Skinner, Julia, Bounacer, Ali, Bond, Jane Ann, Haughton, Michele Fleur, deMicco, Catherine and Wynford-Thomas, David 2004. Opposing effects of mutant ras oncoprotein on human fibroblast and epithelial cell proliferation: implications for models of human tumorigenesis. Oncogene 23 (35) , pp. 5994-5999. 10.1038/sj.onc.1207798

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Abstract

Using microinjection of recombinant protein to directly control 'expression' levels, we have compared the proliferative response to ras oncogene activation in two normal cell types--fibroblast and thyroid epithelial cell--which give rise to human tumours with very low and high frequencies of ras mutation respectively. A concentration-dependent stimulation of DNA synthesis was observed in thyrocytes, matched by an almost perfectly reciprocal inhibition in fibroblasts. A concentration-dependent induction of the cyclin-dependent kinase (CDK) inhibitor p21WAF1 was observed in both cell types, but p16Ink4a was induced by ras only in fibroblasts. This difference could not account for the fibroblast specificity of the growth-inhibitory response, however, since proliferation of p16-deficient fibroblasts was also inhibited by mutant ras. We conclude that the striking contrast in proliferative response to ras between fibroblasts and thyroid epithelial cells cannot readily be explained by differential induction of either of the two key CDK inhibitors, p16Ink4a and p21WAF1, but is consistent with a differential ability of p21WAF1 to antagonize ras-induced mitogenic signals in the two cell types. Such tissue-specific differences provide an attractive explanation for the observed specificity of ras mutation for particular human tumour types, and emphasize the inappropriateness of fibroblasts as a model for ras-induced tumorigenesis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Uncontrolled Keywords:	ras oncogene ; cell cycle ; human tumours ; epithelial ; fibroblast ; senescence
Publisher:	Nature Publishing
ISSN:	0950-9232
Last Modified:	18 Oct 2017 08:15
URI:	https://orca.cardiff.ac.uk/id/eprint/173

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