Growth stimulation of murine fibroblasts by TGF-beta1 depends on the expression of a functional p53 protein.
Transforming Growth Factor-beta1 (TGF-beta1) inhibits the proliferation of most cells, but stimulates some mesenchymal cell types, including murine NIH3T3 fibroblasts. We show here that TGF-beta1 growth stimulation of NIH3T3 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-beta1 growth stimulation of NIH3T3 cells is not observed when these cells are transfected with plasmids expressing either a mutant Large T, unable to bind P53, or the E1A adenovirus oncoprotein which binds the retinoblastoma protein pRB but not P53. But when the TGF-beta1-growth stimulated cells are transfected with a plasmid expressing a mutant form of Large T capable 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 cells are growth-inhibited by TGF-beta1. The cdk inhibitor p21Waf is decreased in TGF-beta1-stimulated NIH3T3 fibroblasts and increased in TGF-beta1-inhibited SV40-transformed cells. Finally, we show that T12 fibroblasts, from a P53 knockout mouse, are growth inhibited by TGF-beta1 and that they remain so upon transfection with a P53 which is mutant at restrictive temperature, but become growth-stimulated by this factor at permissive temperature when P53 is functional. These data strongly suggest that growth-stimulation of fibroblasts by TGF-beta1 depends on the presence of a functional P53 protein and that inversion of this response occurs if P53 is absent or inactivated.
Dkhissi
F
F
UPR9079 du CNRS, Villejuif, France.
Raynal
S
S
Jullien
P
P
Lawrence
D A
DA
D016475:3T3 Cells; D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D013539:Simian virus 40 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins