Loss of atm radiosensitizes multiple p53 null tissues.
An unusual clinical finding in ataxia-telangiectasia, a human disorder caused by mutations in atm, is exquisite sensitivity to gamma irradiation. By contrast, homozygous deletion of p53 is marked by radiation resistance in certain tissue compartments. Previous studies (A. J. Levine, Cell, 88: 323-331, 1997) have shown that, in vitro, p53-deficient bone marrow cells are resistant to gamma irradiation. Furthermore, the gastrointestinal radiosensitization engendered by the loss of atm has recently been shown (C. H. Westphal et al., Nat. Genet., 16: 397-401, 1997) to be independent of p53. Expanding on previous work, we have looked at in vivo bone marrow resistance in p53-deficient mice. Our results indicate that inbred FVB strain p53 null mice survive lethal irradiation doses because of bone marrow resistance. Moreover, the deletion of atm radiosensitizes even p53 null bone marrow and mouse embryonic fibroblast cells. The results presented here argue that the loss of atm radiosensitizes multiple tissues in a p53-independent manner. Hence, functional inhibition of atm in p53 null and p53 wild-type human tumors may be a useful adjunct to gamma irradiation-based antitumor therapy.
Westphal
C H
CH
Department of Genetics and HHMI, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hoyes
K P
KP
Canman
C E
CE
Huang
X
X
Kastan
M B
MB
Hendry
J H
JH
Leder
P
P
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001853:Bone Marrow / Q000528:radiation effects; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000528:radiation effects; D017353:Gene Deletion; D016158:Genes, p53; D006579:Heterozygote; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D011836:Radiation Tolerance; D013997:Time Factors; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases