Crosstalk between p53 family members and TGF-beta signaling in development and cancer

The p53 tumor suppressor is the focus of intense investigation. It is considered a latent transcription factor that must be activated through post-translational modifications induced by extracellular stimuli, such as radiations, or genotoxic stress. Recently, however, the in vivo role of acute DNA damage in p53 activation has been questioned, leaving uncertainty on the identity of the physiological p53 activating inputs. Here we found a direct connection between p53 and Ras signaling in the context of TGF-ß responses. This link is evolutionary conserved. Mechanistically, we found that Ras promotes p53 N-terminal phosphorylation that enables in p53 the ability to recognize TGF-ß activated Smads. The p53/Smad complex regulates the transcription of mesodermal genes during Xenopus embryonic development and the growth arrest gene expression program in adult mammalian epithelial cells. p53 is frequently mutated in cancer, but, at difference with other tumor suppressors, its expression is not lost in tumors. This unusual behavior suggests that mutant-p53 may have neomorphic, "gain-of-function" oncogenic properties, that are still largely enigmatic. Just like p53, TGF-ß is also a double-edged sword, being not only a tumor suppressor but also a potent promoter of malignancy in advanced tumors. This intriguing analogy prompted us to test if mutant-p53 also functionally cooperates with TGF-ß in tumor progression. We found that migration and invasion induced by TGF-ß in breast cancer cells requires mutant-p53 expression. Biochemically, TGF-ß induces the formation of a mutant-p53/Smad complex, whose function is to entrap p63/p73 into transcriptionally inactive mutant-p53/Smad/p63-p73 complexes. Our data indicate that these p53 family members may act as metastasis suppressors. In the absence of active p63/p73, TGF-ß is proficient in activating a vast repertoire of genes involved in migration, adhesion and cell-polarity. Finally, our study unveiled a new set of genes that prevents migration and invasion with potential prognostic value