Interaction between p53 and TGF beta 1 in control of epithelial cell proliferation.
Although loss of sensitivity to transforming growth factor beta (TGF beta) may be a key step in the escape of epithelial tumours from normal growth control, the intracellular signals determining responsiveness remain controversial, particularly the role of p53. We have investigated this question using thyroid epithelial lines as a model. We analysed (i) human thyroid cancer cell lines having either wild-type (wt) or mutant p53; (ii) rat thyroid lines derived by spontaneous immortalisation following introduction of mutant H-ras, which exhibit high levels of wt p53 but loss of p53-mediated cell-cycle control. Loss of response to TGF beta 1 was found in all human lines bearing mutant p53, and in the majority of the functionally equivalent rat lines, consistent with a role of wt p53 in mediating response. However, introduction of a dominant negative p53 mutant into TGF beta 1 responsive human lines containing wt p53 did not reduce responsiveness, demonstrating that p53 function is not necessary for TGF beta 1 response. On the other hand, expression of a temperature-sensitive (ts) p53 gene in a partially-responsive rat line demonstrated a highly significant modulation of TGF beta response, which fell from 65% inhibition of 3H-thymidine labelling index at 32.5 degrees C (wt p53 conformation) to only 14% at 37.5 degrees C (mutant conformation). The results suggest that p53 and TGF beta generate separate but interacting inhibitory signals, i.e. that p53 modulates but does not mediate TGF beta response. This conclusion explains previous conflicting data and is consistent with current models of cell cycle control by multiple inhibitors of cyclin-dependent kinases.
Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, UK.
J P
JP
Blaydes
M
M
Schlumberger
D
D
Wynford-Thomas
F S
FS
Wyllie
D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D051381:Rats; D013696:Temperature; D013964:Thyroid Neoplasms / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53