Effect of serum growth factors and phorbol ester on growth and survival of human thyroid epithelial cells expressing mutant ras.
We previously demonstrated a high incidence of ras mutation in thyroid follicular (epithelial) cell neoplasms and showed that expression of mutant ras is a potent mitogenic stimulus for normal human follicular cells in culture. Here we show that induction of cell proliferation in primary follicular cells by a mutant human Ha-ras (val 12) expressed from a retroviral vector was absolutely dependent on the presence of serum growth factors. Induction of DNA synthesis showed partial dependence. Mutant ras-induced growth was also inhibited by exposure to phorbol ester at concentrations sufficient to downregulate protein kinase C. More importantly, we observed an unexpected toxic effect of phorbol ester in this system that was specific to cells expressing mutant ras. This has potential significance both for elucidating the basic mechanism of ras action in epithelial cells and also as a pointer to a novel therapeutic strategy.
Bond
J
J
CRC Thyroid Tumour Biology Research Group, Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom.
Dawson
T
T
Lemoine
N
N
Wynford-Thomas
D
D
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000254:growth & development; D011905:Genes, ras / Q000187:drug effects*; D006133:Growth Substances / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*
D006133:Growth Substances; D013755:Tetradecanoylphorbol Acetate