GENETIC INTERACTIONS BETWEEN ATM AND P53 INFLUENCE CELLULAR PROLIFERATION AND IRRADIATION-INDUCED CELL-CYCLE CHECKPOINTS

Ataxia-telangiectasia and Li-Fraumeni syndrome, pleiotropic disorders caused by mutations in the genes atm and p53, share a marked increase in cancer rates. A number of studies have argued for an interaction be tween these two genes (for comprehensive reviews, see M. S. Meyn, Canc er Res., 55: 5991-6001, 1995, and M. F. Lavin and Y. Shiloh, Annu. Rev ., Immunol., 15: 177-202, 1996). Specifically, atm is placed upstream of p53 in mediating G(1)-S tell cycle checkpoint control, and both afm and p53 are believed to influence cellular proliferation. To analyze the genetic interactions of atm and p53, mouse embryonic fibroblasts ( MEFs) homozygously deficient for both atm and p53 were used to assess cell cycle and growth control. These double-null fibroblasts prolifera te rapidly and fail to exhibit the premature growth arrest seen with a tm-null MEFs. MEFs null for both atm and p53 do not express any p21(ci pl/wafl), showing that p53 is required for p21(cipl/wafl) expression i n an atm-null background. By contrast, homozygous loss of either atm, p53, or both results in similar abnormalities of the irradiation-induc ed G(1)-S cell cycle checkpoint. Our results suggest two separate path ways of interaction between atm and p53, one linear, involving G(1)-S cell cycle control, and another more complex, involving aspects of gro wth regulation.