ATM regulates target switching to escalating doses of radiation in the intestines.
Although stem cells succumbing to reproductive death are assumed to be the single relevant targets in radiation tissue damage, recent studies showed intestinal stem cell damage is conditionally linked to crypt endothelial apoptosis, defining a two-target model. Here we report that when mouse intestines were protected against microvascular apoptosis, radiation switched as the dose escalated to a previously unrecognized crypt stem cell target, activating ceramide synthase-mediated apoptosis to initiate intestinal damage. Whereas ataxia telangiectasia-mutated (ATM) kinase normally represses ceramide synthase, its derepression in Atm(-/-) mice increased crypt stem cell radiosensitivity 3.7-fold without sensitizing the microvascular response. Discovery of this intestinal radiosensitivity mechanism allowed design of an antisense Atm oligonucleotide treatment which phenocopied the Atm(-/-) mouse, reordering ceramide synthase-mediated stem cell death to become the first-line gastrointestinal response of wild-type littermates. These experiments indicate that tissues operate multiple potential targets activated consecutively according to their inherent radiosensitivities that may be reordered therapeutically to control radiation tissue responses.
Ch'ang
Hui-Ju
HJ
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Maj
Jerzy G
JG
Paris
François
F
Xing
H Rosie
HR
Zhang
Jianjun
J
Truman
Jean-Philip
JP
Cardon-Cardo
Carlos
C
Haimovitz-Friedman
Adriana
A
Kolesnick
Richard
R
Fuks
Zvi
Z
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation / Q000528:radiation effects; D006652:Histological Techniques; D007583:Jejunum / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000532:radiotherapy*; D009841:Oligonucleotides; D010088:Oxidoreductases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000235:genetics; D013234:Stem Cells / Q000528:radiation effects*; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014916:Whole-Body Irradiation
D018797:Cell Cycle Proteins; D002518:Ceramides; D004268:DNA-Binding Proteins; D009841:Oligonucleotides; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases