TGF beta 1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner
2006 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 5, no 23, 2787-2795 p.Article in journal (Refereed) Published
ATM, a DNA-damage sensitive kinase and p53, are frequently inactivated in a variety of cancers as they together with gamma H2AX are critical guardians against DNA damage. Here, we report of a functional cross-talk between the cytokine TGF beta and p53, leading to apoptosis of epithelial cells, involving Smad7, a TGF beta target gene, p38 MAP kinase, and ATM. Using ectopic expression of p53, siRNA for Smad7, p38a(-/-) deficient cells and specific inhibitors, we show that TGF-beta 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 TGF beta treatment, facilitating their activation. Smad7. colocalizes with gamma H2AX 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.
Place, publisher, year, edition, pages
2006. Vol. 5, no 23, 2787-2795 p.
apoptosis, prostate cancer, p53, Smad, ATM
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-147029ISI: 000242897800016PubMedID: 17172861OAI: oai:DiVA.org:uu-147029DiVA: diva2:399788