LOSS OF P21 INCREASES SENSITIVITY TO IONIZING-RADIATION AND DELAYS THE ONSET OF LYMPHOMA IN ATM-DEFICIENT MICE

Ataxia telangiectasia (AT) is an autosomal recessive disorder characte rized by growth retardation, cerebellar ataxia, oculocutaneous telangi ectasias, 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 cell ular senescence and response to gamma-radiation-induced DNA damage. To study the role of p21 in ATM-mediated signal transduction pathways, w e examined the combined effect of the genetic loss of atm and p21 on g rowth control, radiation sensitivity, and tumorigenesis. As might have been expected, our data provide evidence that p21 modifies the in vit ro senescent response seen in AT fibroblasts. Further, it is a downstr eam effector of ATM-mediated growth control. In addition, however, we find that loss of p21 in the context of an atm-deficient mouse leads t o 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 apopt osis seen in tumor cells and in the irradiated intestinal epithelium o f mice doubly null for atm and p21. Thus, loss of p21 seems to contrib ute to tumor suppression by a mechanism that operates via a sensitized apoptotic response. These results have implications for cancer therap y in general and AT patients in particular.