Loss of growth control by TGF-beta occurs at a late stage of mouse skin carcinogenesis and is independent of ras gene activation.
The relationship between the expression of a mutant ras gene in epithelial cells and loss of responsiveness to the negative effects of transforming growth factor beta (TGF-beta) is presently unclear. We have investigated this question using a series of cell lines derived from benign and malignant mouse skin tumours which express mutant forms of the H-ras gene. Immortalised, non-tumorigenic mouse epidermal cells respond to TGF-beta by cessation of growth, whereas in a series of malignant carcinoma lines the response was substantially reduced. Introduction of a mutant H-ras gene into the immortalised cells did not lead to any appreciable change in TGF-beta responsiveness, suggesting that initiation of carcinogenesis by ras mutation does not directly alter growth control by this pathway. Of two non-tumorigenic papilloma lines tested which had mutant H-ras genes, one retained complete sensitivity to TGF-beta, whereas the other showed a similar response to carcinomas. We conclude that growth control by TGF-beta is lost at a relatively late stage of carcinogenesis in this system, and is independent of ras gene activation.
Haddow
S
S
CRC Beatson Laboratories, Beatson Institute for Cancer Research, Bearsden, Glasgow, UK.
Fowlis
D J
DJ
Parkinson
K
K
Akhurst
R J
RJ
Balmain
A
A
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism; D004848:Epithelium / Q000473:pathology / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D011905:Genes, ras / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics; D012878:Skin Neoplasms / Q000473:pathology* / Q000503:physiopathology; D013936:Thymidine / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014316:Tritium; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D016212:Transforming Growth Factor beta; D014316:Tritium; D013936:Thymidine