Atm deficiency affects both apoptosis and proliferation to augment Myc-induced lymphomagenesis.
Myc oncoproteins are commonly activated in malignancies and are sufficient to provoke many types of cancer. However, the critical mechanisms by which Myc contributes to malignant transformation are not clear. DNA damage seems to be an important initiating event in tumorigenesis. Here, we show that although Myc does not directly induce double-stranded DNA breaks, it does augment activation of the Atm/p53 DNA damage response pathway, suggesting that Atm may function as a guardian against Myc-induced transformation. Indeed, we show that Atm loss augments Myc-induced lymphomagenesis and impairs Myc-induced apoptosis, which normally harnesses Myc-driven tumorigenesis. Surprisingly, Atm loss also augments the proliferative response induced by Myc, and this augmentation is associated with enhanced suppression of the expression of the cyclin-dependent kinase inhibitor p27(Kip1). Therefore, regulation of cell proliferation and p27(Kip1) seems to be a contributing mechanism by which Atm holds tumor formation in check.
Maclean
Kirsteen H
KH
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Kastan
Michael B
MB
Cleveland
John L
JL
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000528:radiation effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency*; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D010766:Phosphorylation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases