Radiation response of neural precursor cells: linking cellular sensitivity to cell cycle checkpoints, apoptosis and oxidative stress.
Therapeutic irradiation of the brain can cause a progressive cognitive dysfunction that may involve defects in neurogenesis. In an effort to understand the mechanisms underlying radiation-induced stem cell dysfunction, neural precursor cells isolated from the adult rat hippocampus were analyzed for acute (0-24 h) and chronic (3-33 days) changes in apoptosis and reactive oxygen species (ROS) after exposure to X rays. Irradiated neural precursor cells exhibited an acute dose-dependent apoptosis accompanied by an increase in ROS that persisted over a 3-4-week period. The radiation effects included the activation of cell cycle checkpoints that were associated with increased Trp53 phosphorylation and Trp53 and p21 (Cdkn1a) protein levels. In vivo, neural precursor cells within the hippocampal dentate subgranular zone exhibited significant sensitivity to radiation. Proliferating precursor cells and their progeny (i.e. immature neurons) exhibited dose-dependent reductions in cell number. These reductions were less severe in Trp53-null mice, possibly due to the disruption of apoptosis. These data suggest that the apoptotic and ROS responses may be tied to Trp53-dependent regulation of cell cycle control and stress-activated pathways. The temporal coincidence between in vitro and in vivo measurements of apoptosis suggests that oxidative stress may provide a mechanistic explanation for radiation-induced inhibition of neurogenesis in the development of cognitive impairment.
Limoli
Charles L
CL
Department of Radiation Oncology, University of California, San Francisco, California 94103-0806, USA. Limoli@itsa.ucsf.edu
Giedzinski
Erich
E
Rola
Radoslaw
R
Otsuka
Shinji
S
Palmer
Theo D
TD
Fike
John R
JR
D000222:Adaptation, Physiological / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D002454:Cell Differentiation / Q000528:radiation effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D006624:Hippocampus / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects*; D009474:Neurons / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects*; D018384:Oxidative Stress / Q000528:radiation effects; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014965:X-Rays
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53