title: Loss of p21 increases sensitivity to ionizing radiation and delays the onset of lymphoma in atm-deficient mice.
abstract: Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by growth retardation, cerebellar ataxia, oculocutaneous telangiectasias, and a high incidence of lymphomas and leukemias. In addition, AT patients are sensitive to ionizing radiation. Atm-deficient mice recapitulate most of the AT phenotype. p21(cip1/waf1 )(p21 hereafter), an inhibitor of cyclin-dependent kinases, has been implicated in cellular senescence and response to gamma-radiation-induced DNA damage. To study the role of p21 in ATM-mediated signal transduction pathways, we examined the combined effect of the genetic loss of atm and p21 on growth control, radiation sensitivity, and tumorigenesis. As might have been expected, our data provide evidence that p21 modifies the in vitro senescent response seen in AT fibroblasts. Further, it is a downstream effector of ATM-mediated growth control. In addition, however, we find that loss of p21 in the context of an atm-deficient mouse leads to a delay in thymic lymphomagenesis and an increase in acute radiation sensitivity in vivo (the latter principally because of effects on the gut epithelium). Modification of these two crucial aspects of the ATM phenotype can be related to an apparent increase in spontaneous apoptosis seen in tumor cells and in the irradiated intestinal epithelium of mice doubly null for atm and p21. Thus, loss of p21 seems to contribute to tumor suppression by a mechanism that operates via a sensitized apoptotic response. These results have implications for cancer therapy in general and AT patients in particular.
authors.affiliation: Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Y A
authors.initials: YA
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Elson
authors.forename: P
authors.initials: P
authors.lastname: Leder
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004268:DNA-Binding Proteins; D005347:Fibroblasts; D017353:Gene Deletion; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases