title: Fragments of ATM which have dominant-negative or complementing activity.
abstract: The ATM protein has been implicated in pathways controlling cell cycle checkpoints, radiosensitivity, genetic instability, and aging. Expression of ATM fragments containing a leucine zipper motif in a human tumor cell line abrogated the S-phase checkpoint after ionizing irradiation and enhanced radiosensitivity and chromosomal breakage. These fragments did not abrogate irradiation-induced G1 or G2 checkpoints, suggesting that cell cycle checkpoint defects alone cannot account for chromosomal instability in ataxia telangiectasia (AT) cells. Expression of the carboxy-terminal portion of ATM, which contains the PI-3 kinase domain, complemented radiosensitivity and the S-phase checkpoint and reduced chromosomal breakage after irradiation in AT cells. These observations suggest that ATM function is dependent on interactions with itself or other proteins through the leucine zipper region and that the PI-3 kinase domain contains much of the significant activity of ATM.
authors.affiliation: The Johns Hopkins Oncology Center, Baltimore, Maryland 21205, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Morgan
authors.forename: C
authors.initials: C
authors.lastname: Lovly
authors.forename: T K
authors.initials: TK
authors.lastname: Pandita
authors.forename: Y
authors.initials: Y
authors.lastname: Shiloh
authors.forename: M B
authors.initials: MB
authors.lastname: Kastan
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics / Q000503:physiopathology*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002869:Chromosome Aberrations; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins; D016158:Genes, p53; D005816:Genetic Complementation Test; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004247:DNA; D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human