The tumor suppressor p53 abrogates Smad-dependent collagen gene induction in mesenchymal cells

摘要: The pleiotropic cytokine transforming growth factor-β (TGF-β) is a potent inducer of collagen synthesis and implicated in the pathogenesis fibrosis. Acting concert with transcriptional coactivators p300/CBP, Smads mediate TGF-β stimulation human dermal fibroblasts. Little information exists regarding positive negative modulation physiological responses. Because tumor suppressor p53 connective tissue homeostasis, here we examined regulation gene expression by p53. Forced ectopic fibroblasts repressed basal TGF-β-stimulated expression, whereas absence cellular was associated significantly enhanced activity Type I (COL1A2) synthesis. Ectopic also promoter driven minimal Smad-binding elements, suggesting that modulated Smad-dependent intracellular signaling. Inhibition not due to altered levels, phosphorylation, or nuclear translocation Smads. Treatment etoposide, p53, abrogated COL1A2 p53-dependent manner. Overexpression coactivator p300 rescued overexpressing Furthermore, ligand-induced interaction Smad3 its cognate DNA element recruitment DNA-protein complex assembled on were markedly reduced p53-overexpressing Collectively, these results indicate, for first time, selective endogenous repressor TGF-β-regulated ligand-dependent may be one targets p53-mediated inhibition These findings suggest novel important physiologic function fibrotic