EFFECTS OF TRANSFORMING GROWTH-FACTOR-BETA-1 ON GROWTH-REGULATORY GENES IN TUMOR-DERIVED HUMAN ORAL KERATINOCYTES

This study examined the effect of transforming growth factor beta-1 (T GF-beta 1) on c-myc, RB1, junB and p53 expression together with pRb ph osphorylation, in carcinoma-derived and normal human oral keratinocyte s with a range of inhibitory responses to this ligand. Amplification o f c-myc was observed in eight of eight tumour-derived cell lines and r esulted in corresponding mRNA expression. The down-regulation of c-myc expression by TGF-beta 1 predominantly reflected growth inhibition by TGF-beta 1, but in two of eight tumour-derived cell lines which were partially responsive to TGF-beta 1 c-myc expression was unaltered by t his ligand. While RB1 mRNA levels were unaltered by TGF-beta 1, the li gand caused the accumulation of the underphosphorylated form of the Rb protein in all cells irrespective of TGF-beta 1-induced growth arrest . junB expression was up-regulated by TGF-beta 1 in cells with a range of growth inhibitory responses. All cells contained mutant p53. TGF-b eta 1 did not affect p53 mRNA expression in both tumour-derived and no rmal keratinocytes and there was no alteration in p53 protein levels i n keratinocytes expressing stable p53 protein following TGF-beta 1 tre atment. The data indicate that TGF-beta-induced growth control can exi st independently of the presence of mutant p53 and the control of Rb p hosphorylation and c-myc down-regulation. It may be that TGF-beta grow th inhibition occurs via multiple mechanisms and that the loss of one pathway during tumour progression does not necessarily result in the a brogation of TGF-beta-induced growth control.