p53 controls radiation-induced gastrointestinal syndrome in mice independent of apoptosis.
Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells affected by radiation to cause the GI syndrome are derived from the epithelium or endothelium and whether the target cells die by apoptosis or other mechanisms are controversial issues. Studying mouse models, we found that selective deletion of the proapoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after sub-total-body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not from endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by the death of GI epithelial cells and that these epithelial cells die by a mechanism that is regulated by p53 but independent of apoptosis.
Kirsch
David G
DG
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Santiago
Philip M
PM
di Tomaso
Emmanuelle
E
Sullivan
Julie M
JM
Hou
Wu-Shiun
WS
Dayton
Talya
T
Jeffords
Laura B
LB
Sodha
Pooja
P
Mercer
Kim L
KL
Cohen
Rhianna
R
Takeuchi
Osamu
O
Korsmeyer
Stanley J
SJ
Bronson
Roderick T
RT
Kim
Carla F
CF
Haigis
Kevin M
KM
Jain
Rakesh K
RK
Jacks
Tyler
T
D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects*; D017353:Gene Deletion; D016158:Genes, p53; D007410:Intestinal Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects*; D007421:Intestine, Small / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects*; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein