p53 Controls Radiation-Induced Gastrointestinal Syndrome in Mice Independent of Apoptosis

David G. Kirsch,^1,2,3,* Philip M. Santiago,¹ Emmanuelle di Tomaso,² Julie M. Sullivan,³ Wu-Shiun Hou,^1, Talya Dayton,¹ Laura B. Jeffords,³ Pooja Sodha,¹ Kim L. Mercer,¹ Rhianna Cohen,¹ Osamu Takeuchi,⁴ Stanley J. Korsmeyer,^4, Roderick T. Bronson,⁵ Carla F. Kim,^1, Kevin M. Haigis,^1,|| Rakesh K. Jain,² Tyler Jacks^1,6,¶

Abstract: 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.

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
³ Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27708, USA.
⁴ Dana Farber Cancer Institute, Boston, MA 02115, USA.
⁵ Tufts University School of Medicine and Veterinary Medicine, North Grafton, MA 05136, USA.
⁶ Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

Present address: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.

Deceased.

Present address: Department of Genetics, Harvard Medical School and Stem Cell Program, Children’s Hospital, Boston, MA 02118, USA.

||Present address: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.

^¶ To whom correspondence should be addressed. E-mail: tjacks{at}mit.edu

The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans.

V. Pant, A. Quintas-Cardama, and G. Lozano (2012)
Blood 120, 5118-5127
 |  Abstract »  |  Full Text »  |  PDF »

Targeting Protein Tyrosine Kinase 6 Enhances Apoptosis of Colon Cancer Cells following DNA Damage.

J. J. Gierut, P. S. Mathur, W. Bie, J. Han, and A. L. Tyner (2012)
Mol. Cancer Ther. 11, 2311-2320
 |  Abstract »  |  Full Text »  |  PDF »

p53 Functions in Endothelial Cells to Prevent Radiation-Induced Myocardial Injury in Mice.

C.-L. Lee, E. J. Moding, K. C. Cuneo, Y. Li, J. M. Sullivan, L. Mao, I. Washington, L. B. Jeffords, R. C. Rodrigues, Y. Ma, et al. (2012)
Science Signaling 5, ra52
 |  Abstract »  |  Full Text »  |  PDF »

Omcg1 is critically required for mitosis in rapidly dividing mouse intestinal progenitors and embryonic stem cells.

T. Leguillier, S. Vandormael-Pournin, J. Artus, M. Houlard, C. Picard, F. Bernex, S. Robine, and M. Cohen-Tannoudji (2012)
Biology Open 1, 648-657
 |  Abstract »  |  Full Text »  |  PDF »

The diagnostic value of [18F]-FDG-PET/CT in hematopoietic radiation toxicity: a Tibet minipig model.

C. Chen, L.-M. Yan, K.-Y. Guo, Y.-J. Wang, F. Zou, W.-W. Gu, H. Tang, Y.-L. Li, and S.-J. Wu (2012)
J Radiat Res 53, 537-544
 |  Abstract »  |  Full Text »  |  PDF »

Darinaparsin: Solid Tumor Hypoxic Cytotoxin and Radiosensitizer.

J. Tian, H. Zhao, R. Nolley, S. W. Reese, S. R. Young, X. Li, D. M. Peehl, and S. J. Knox (2012)
Clin. Cancer Res. 18, 3366-3376
 |  Abstract »  |  Full Text »  |  PDF »

Delta-Like Ligand 4-Notch Blockade and Tumor Radiation Response.

S. K. Liu, S. A. S. Bham, E. Fokas, J. Beech, J. Im, S. Cho, A. L. Harris, and R. J. Muschel (2011)
J Natl Cancer Inst 103, 1778-1798
 |  Abstract »  |  Full Text »  |  PDF »

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets.

E. C. Josefsson, C. James, K. J. Henley, M. A. Debrincat, K. L. Rogers, M. R. Dowling, M. J. White, E. A. Kruse, R. M. Lane, S. Ellis, et al. (2011)
J. Exp. Med. 208, 2017-2031
 |  Abstract »  |  Full Text »  |  PDF »

Uncoupling p53 Functions in Radiation-Induced Intestinal Damage via PUMA and p21.

B. J. Leibowitz, W. Qiu, H. Liu, T. Cheng, L. Zhang, and J. Yu (2011)
Mol. Cancer Res. 9, 616-625
 |  Abstract »  |  Full Text »  |  PDF »

Decreasing the Adverse Effects of Cancer Therapy: National Cancer Institute Guidance for the Clinical Development of Radiation Injury Mitigators.

B. Movsas, B. Vikram, M. Hauer-Jensen, J. E. Moulder, E. Basch, S. L. Brown, L. A. Kachnic, A. P. Dicker, C. N. Coleman, and P. Okunieff (2011)
Clin. Cancer Res. 17, 222-228
 |  Abstract »  |  Full Text »  |  PDF »

Sphingosine-1-Phosphate Activates the AKT Pathway to Protect Small Intestines from Radiation-Induced Endothelial Apoptosis.

S. Bonnaud, C. Niaudet, F. Legoux, I. Corre, G. Delpon, X. Saulquin, Z. Fuks, M.-H. Gaugler, R. Kolesnick, and F. Paris (2010)
Cancer Res. 70, 9905-9915
 |  Abstract »  |  Full Text »  |  PDF »