ATM regulates target switching to escalating doses of radiation in the intestines Journal Article
| Authors: | Chang, H. J.; Maj, J. G.; Paris, F.; Xing, H. R.; Zhang, J.; Truman, J. P.; Cordon-Cardo, C.; Haimovitz-Friedman, A.; Kolesnick, R.; Fuks, Z. |
| Article Title: | ATM regulates target switching to escalating doses of radiation in the intestines |
| Abstract: | 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. |
| Keywords: | controlled study; dna-binding proteins; dose response; nonhuman; radiation dose; neoplasms; mouse; animals; cell cycle proteins; mice; mice, knockout; animal tissue; apoptosis; animal experiment; animal model; enzyme activation; radiation injury; wild type; mice, inbred c57bl; histological techniques; dose-response relationship, radiation; animalia; stem cell; endothelial cells; protein-serine-threonine kinases; nucleotide sequence; tumor suppressor proteins; atm protein; stem cells; radiosensitivity; oxidoreductases; ataxia; jejunum; intestine injury; whole-body irradiation; oligonucleotides; ceramides; intestine crypt; ataxia telangiectasia; sphingosine acyltransferase; radiation tolerance; antisense oligonucleotide; tumor stem cell assay |
| Journal Title: | Nature Medicine |
| Volume: | 11 |
| Issue: | 5 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2005-05-01 |
| Start Page: | 484 |
| End Page: | 490 |
| Language: | English |
| DOI: | 10.1038/nm1237 |
| PUBMED: | 15864314 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 57" - "Export Date: 24 October 2012" - "CODEN: NAMEF" - "Molecular Sequence Numbers: GENBANK: NM_007499;" - "Source: Scopus" |
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