Opposing effects of mutant ras oncoprotein on human fibroblast and epithelial cell proliferation: implications for models of human tumorigenesis.
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.
Skinner
Julia
J
Cancer Research UK Laboratories, Department of Pathology, University of Wales College of Medicine, Cardiff CF14 4XN, UK.
Bounacer
Ali
A
Bond
Jane A
JA
Haughton
Michele F
MF
deMicco
Catherine
C
Wynford-Thomas
David
D
D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D019942:Genes, p16; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000473:pathology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins