title: Upregulation of FasL and apoptosis in thymic lymphomas in Atm knock-in mice.
abstract: Several members of the phosphatidylinositol 3-kinase family play key roles in recognising and responding to damage in DNA, induced by a variety of chemicals and other agents. One of these, ATM, the product of the gene mutated in the human genetic disorder ataxia-telangiectasia (A-T), recognises double strand breaks in DNA caused by ionizing radiation and radiomimetic chemicals. In order to study DNA damage recognition and the abnormalities of genome instability and cancer predisposition that occur in A-T patients, we generated a mouse model expressing a mutant form of Atm corresponding to a common human mutation. In this model, a 9 nucleotide in-frame deletion was introduced into the Atm gene and has been designated Atm-Delta SRI. These animals had a longer lifespan than Atm gene disrupted mice (Atm(-/-)) and they developed less thymic lymphomas. A characteristic of the lymphomas appearing in Atm-Delta SRI mice was an increased rate of apoptosis compared to the corresponding tumours in Atm(-/-) mice. Increased expression of FasL in these tumours may account for the higher levels of apoptosis. These results demonstrate that expression of mutant Atm in mice gives rise to phenotypic differences compared to Atm(-/-) mice and has implications for heterogeneity described in the human syndrome.
authors.affiliation: The Queensland Cancer Fund Research Laboratories, The Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Brisbane, Qld. 4029, Australia. martinl@qimr.edu.au
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
authors.forename: Kevin
authors.initials: K
authors.lastname: Spring
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002869:Chromosome Aberrations; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D017353:Gene Deletion; D005822:Genetic Vectors; D006720:Homozygote; D015151:Immunoblotting; D016399:Lymphoma, T-Cell / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011494:Protein Kinases