Editors' ChoiceDevelopment

TGF-β and p53 Partner Up

Science's STKE  13 May 2003:
Vol. 2003, Issue 182, pp. tw190-TW190
DOI: 10.1126/stke.2003.182.tw190

Cell proliferation and fate during embryogenesis are regulated in part by members of the transforming growth factor-beta (TGF-β) family. These factors act through serine-threonine kinase receptors at the cell surface, causing the phosphorylation, activation, and translocation of intracellular Smad protein to the nucleus, where they control gene expression. But the mechanisms that ensure specificity of the transcriptional response to TGF-β ligands has not been clear. To the list of transcriptional regulators that Smad partners with, Cordenonsi et al. now add the tumor suppressor protein p53, also a transcriptional regulator. The study reports that p53 binds to Smad2 to control the expression of several TGF-β target genes in Xenopus embryos and human cells. Ectopic expression of p53 or Smad2 in early Xenopus embryos had similar phenotypic effects, and expression of p53 with a dominant-negative form of Smad2 blocked the TGF-β-like inductions triggered by p53. Reducing the expression of p53 in embryos with antisense oligonucleotides blocked mesoderm differentiation normally induced by TGF-β ligands. Reducing p53 expression in cultured human cells with small interfering RNA also affected a subset of TGF-β target genes, including the cyclin-dependent kinase p21WAF, a regulator of growth arrest. Endogenous interaction between p53 and Smad proteins was observed, and the authors propose that the factors converge at their cognate sites within the promoter region of gene targets, resulting in synergistic transcriptional activation. The study suggests that the inactivation of p53 may underlie a coincident loss of TGF-β-suppressing effects in certain cancer cells.

M. Cordenonsi, S. Dupont, S. Maretto, A. Insinga, C. Imbriano, S. Piccolo, Links between tumor suppressors: p53 is required for TGF-β gene responses by cooperating with Smads. Cell 113, 310-314 (2003). [Online Journal]