Effects of transforming growth factor β-1 on growth-regulatory genes in tumour-derived human oral keratinocytes

This study examined the effect of transforming growth factor β-1 (TGF-β 1) on c-myc, RB1, junB and p53 expression together with pRb phosphorylation, in carcinoma-derived and normal human oral keratinocytes with a range of inhibitory responses to this ligand. Amplification of c-myc was observed in eight of eight tumour-derived cell lines and resulted in corresponding mRNA expression. The down-regulation of c-myc expression by TGF-β1 predominantly reflected growth inhibition by TGF-β1, but in two of eight tumour-derived cell lines which were partially responsive to TGF-β1 c-myc expression was unaltered by this ligand. While RB1 mRNA levels were unaltered by TGF-β1, the ligand caused the accumulation of the underphosphorylated form of the Rb protein in all cells irrespective of TGF-β1-induced growth arrest. junB expression was up-regulated by TGF-β1 in cells with a range of growth inhibitory responses. All cells contained mutant p53. TGF-β1 did not affect p53 mRNA expression in both tumour-derived and normal keratinocytes and there was no alteration in p53 protein levels in keratinocytes expressing stable p53 protein following TGF-β1 treatment. The data indicate that TGF-β-induced growth control can exist independently of the presence of mutant p53 and the control of Rb phosphorylation and c-myc down-regulation. It may be that TGF-β growth inhibition occurs via multiple mechanisms and that the loss of one pathway during tumour progression does not necessarily result in the abrogation of TGF-β-induced growth control.