Radiation-induced apoptosis in developing mouse retina exhibits dose-dependent requirement for ATM phosphorylation of p53.
Ionizing radiation (IR) induces DNA breakage to activate cell cycle checkpoints, DNA repair, premature senescence or cell death. A master regulator of cellular responses to IR is the ATM kinase, which phosphorylates a number of downstream effectors, including p53, to inhibit cell cycle progression or to induce apoptosis. ATM phosphorylates p53 directly at Ser15 (Ser18 of mouse p53) and indirectly through other kinases. In this study, we examined the role of ATM and p53 Ser18 phosphorylation in IR-induced retinal apoptosis of neonatal mice. Whole-body irradiation with 2 Gy IR induces apoptosis of postmitotic and proliferating cells in the neonatal retinas. This apoptotic response requires ATM, exhibits p53-haploid insufficiency and is defective in mice with the p53S18A allele. At a higher dose of 14 Gy, retinal apoptosis still requires ATM and p53 but can proceed without Ser18 phosphorylation. These results suggest that ATM activates the apoptotic function of p53 in vivo through alternative pathways depending on IR dose.
Borges
H L
HL
Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
Chao
C
C
Xu
Y
Y
Linden
R
R
Wang
J Y J
JY
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D004249:DNA Damage / Q000502:physiology / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D018507:Gene Expression Regulation, Developmental / Q000502:physiology / Q000528:radiation effects; D016158:Genes, p53 / Q000235:genetics*; D051379:Mice; D010766:Phosphorylation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000254:growth & development / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases