ATM regulates target switching to escalating doses of radiation in the intestines Academic Article uri icon

Overview

MeSH Major

  • Apoptosis
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Neoplasms
  • Oxidoreductases
  • Protein-Serine-Threonine Kinases
  • Stem Cells
  • Tumor Stem Cell Assay
  • Tumor Suppressor Proteins
  • Whole-Body Irradiation

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.

publication date

  • May 2005

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/nm1237

PubMed ID

  • 15864314

Additional Document Info

start page

  • 484

end page

  • 90

volume

  • 11

number

  • 5