TGFβ1-Induced Activation of ATM and p53 Mediates Apoptosis in a Smad7-Dependent Manner

Shouting Zhang, Maria Ekman, Noopur Thakur, Shizhong Bu, Padideh Davoodpour, Susanne Grimsby, Seicchi Tagami, Carl-Henrik Heldin and Marene Landström

volume 5 | issue 23

1 december 2006
Pages: 2787 - 2795

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ATM, a DNA-damage sensitive kinase and p53, are frequently inactivated in a variety of cancers as they together with γH2AX are critical guardians against DNA damage. Here, we report of a functional cross-talk between the cytokine TGFβ and p53, leading to apoptosis of epithelial cells, involving Smad7, a TGF-β target gene, p38 MAP kinase, and ATM. Using ectopic expression of p53, siRNA for Smad7, p38α -/- deficient cells and specific inhibitors, we show that TGF-β induces apoptosis via ATM and p53 in epithelial cells. Intriguingly, Smad7 act as a scaffold protein to promote functional interactions between p38, ATM and p53 upon TGFβ treatment, facilitating their activation. Smad7 colocalizes with γH2AX in DNA damage foci and was required for proper cell cycle checkpoints to prevent genetic instability. Our data imply that Smad7 plays a crucial role upstream of ATM and p53 to protect the genome from insults evoked by extracellular stress.