Growth stimulation of murine fibroblasts by TGF-β1 depends on the expression of a functional p53 protein

Abstract

Transforming Growth Factor-b1 (TGF-b1) inhibits the proliferation of most cells, but stimulates some mesenchymal cell types, including murine NIH3T3 ®broblasts. We show here that TGF-b1 growth stimulation of NIH3T3 ®broblasts 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-b1 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-b1-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-b1. The cdk inhibitor p21Waf is decreased in TGFb1-stimulated NIH3T3 ®broblasts and increased in TGFb1-inhibited SV40-transformed cells. Finally, we show that T12 ®broblasts, from a P53 knockout mouse, are growth inhibited by TGF-b1 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 growthstimulation of ®broblasts by TGF-b1 depends on the presence of a functional P53 protein and that inversion of this response occurs if P53 is absent or inactivated.

Neonatal Hyperoxia Increases Sensitivity of Adult Mice to Bleomycin-Induced Lung Fibrosis

“…TGF-b signaling can drive fibrosis through multiple mechanisms, including prevention of the death of activated T lymphocytes, hence permitting the survival of immune cells that may contribute to inflammation and epithelial injury (43). TGF-b signaling can also stimulate the proliferation of fibroblasts (44), inhibit myofibroblast apoptosis (45), stimulate matrix deposition (46), and promote the epithelial-mesenchymal transition (47,48). Because TGF-b regulates so many biologic processes, to identify a singular mechanism by which it promotes fibrosis has been difficult.…”

Transforming Growth Factor-β Regulates in Vitro Heart Valve Repair by Activated Valve Interstitial Cells

“…18 The signaling mechanism of TGF-␤ in promoting proliferation has been under study for a number of cell types. 25,73,74 In addition to the wellcharacterized Smad pathways in promoting proliferation, non-Smad TGF-␤ signaling pathways are recently found to be also important in regulating fibroblasts proliferation in which TGF-␤ signals through the phosphoinositide-3 kinase (PI3K) pathway leading to phosphorylation of Akt After wounding, VICs at the WE express ␣-SMA, a marker of VIC activation. Activated VICs require TGF-␤ to maintain activation through promoting ␣-SMA mRNA production and protein expression.…”

A Direct Intersection between p53 and Transforming Growth Factor β Pathways Targets Chromatin Modification and Transcription Repression of the α-Fetoprotein Gene

“…Mutation of p53 reduces the ability of TGF-␤1 to inhibit growth of human bronchial epithelial cells (31) and to stimulate the growth of mesenchymal murine fibroblasts (27). TGF-␤1 treatment of rat liver epithelial cells and immortalized human cervical cells induced apoptosis and/or cell cycle arrest, concomitant with p53 activation (61,76).…”