Growth stimulation of murine fibroblasts by TGF-beta 1 depends on the expression of a functional p53 protein

Transforming Growth Factor-beta 1 (TGF-beta 1) inhibits the proliferation o f most cells, but stimulates some mesenchymal cell types, including murine NIH3T3 fibroblasts, We show here that TGF-beta 1 growth stimulation of NIH3 T3 fibroblasts is reversed when these cells are transformed by SV40 or are transfected with a plasmid encoding the SV40 Large T antigen. Inversion of the TGF-beta 1 growth stimulation of NIH3T3 cells is not observed when thes e cells are transfected with plasmids expressing either a mutant Large T, u nable to bind P53, or the E1A adenovirus oncoprotein which binds the retino blastoma protein pRB but not P53, But when the TGF-beta 1-growth stimulated cells are transfected with a plasmid expressing a mutant form of Large T c apable of binding to P53, but not to pRB, or with one expressing the E1B-55 kD adenovirus oncoprotein, which also binds to P53 but not to pRB, the cel ls are growth-inhibited by TGF-beta 1. The cdk inhibitor p21Waf is decrease d in TGF-beta 1-stimulated NIH3T3 fibroblasts and increased in TGF-beta 1-i nhibited SV40-transformed cells. Finally, we show that T12 fibroblasts, fro m a P53 knockout mouse, are growth inhibited by TGF-beta 1 and that they re main so upon transfection with a P53 which is mutant at restrictive tempera ture, but become growth-stimulated by this factor at permissive temperature when P53 is functional. These data strongly suggest that growth-stimulatio n of fibroblasts by TGF-beta 1 depends on the presence of a functional P53 protein and that inversion of this response occurs if P53 is absent or inac tivated.