TGFbeta1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner.
ATM, a DNA-damage sensitive kinase and p53, are frequently inactivated in a variety of cancers as they together with gammaH2AX are critical guardians against DNA damage. Here, we report of a functional cross-talk between the cytokine TGFbeta and p53, leading to apoptosis of epithelial cells, involving Smad7, a TGFbeta target gene p38 MAP kinase, and ATM. Using ectopic expression of p53, siRNA for Smad7, p38alpha-/- 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 TGFbeta treatment, facilitating their activation. Smad7 colocalizes with gammaH2AX 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.
Zhang
Shouting
S
Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Uppsala, Sweden.
Ekman
Maria
M
Thakur
Noopur
N
Bu
Shizhong
S
Davoodpour
Padideh
P
Grimsby
Susanne
S
Tagami
Seicchi
S
Heldin
Carl-Henrik
CH
Landström
Marene
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010768:Phosphoserine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases