Role of p53 in regulating tissue response to radiation by mechanisms independent of apoptosis.
Radiation exposure leads to diverse outcomesin vivoacross different tissues and even within the same cell lineage. The diversity of radiation responsein vivois at least partially attributable to the status of the tumor suppressor p53, a master regulator of cellular response to stress, and activation of its transcriptional targets. In certain cells, such as hematopoietic progenitors and transit amplifying cells in the gastrointestinal epithelium, activation of p53 by radiation triggers the intrinsic pathway of apoptosis. However, in many other cells, activation of p53 by radiation does not result in apoptosis, which underscores the importance of understanding the role of p53 in regulating radiation response through alternative mechanisms. In this review, we summarize recent studies using genetically engineered mice to dissect the role of p53 in 1) cells where its activation is dissociated from the intrinsic pathway of apoptosis, such as hematopoietic stem cells and vascular endothelial cells and 2) tissues where activation of the intrinsic pathway of apoptosis does not promote the acute radiation syndrome, such as the gastrointestinal epithelium. We highlight findings showing that the apoptosis-independent response of p53 to radiationin vivocan contribute to death or survival in a cell-type dependent manner, which underscores the complexity by which p53 regulates the cellular and tissue response to radiation.
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Chang-Lung
CL
Lee
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Jordan M
JM
Blum
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA ; Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
David G
DG
Kirsch
Apoptosis; Cell cycle arrest; Normal tissue injury; Radiation; p53