Adorno, Maddalena (2008) Crosstalk between p53 family members and TGF-beta signaling in development and cancer. [Ph.D. thesis]
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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.
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