c-Abl is required for development and optimal cell proliferation in the context of p53 deficiency

The c-Abl tyrosine kinase and the p53 tumor suppressor protein interact fun ctionally and biochemically in cellular genotoxic stress response pathways and are implicated as downstream mediators of ATM (ataxia-telangiectasia mu tated). This fact led us to study genetic: interactions in vivo between c-A bl and p53 by examining the phenotype of mice and cells deficient in both p roteins. c-Abl-null mice show high neonatal mortality and decreased B lymph ocytes, whereas p53-null mice are prone to tumor development Surprisingly, mice doubly deficient in both c-Abl and p53 are not viable, suggesting that c-Abl and p53 together contribute to an essential function required for no rmal development. Fibroblasts lacking both c-Abl and p53 were similar to fi broblasts deficient in p53 alone, showing loss of the G(1)/S cell-cycle che ckpoint and similar clonogenic survival after ionizing radiation. Fibroblas ts deficient in both c-Abl and p53 show reduced growth in culture, as manif ested by reduction in the rate of proliferation, saturation density, and co lony formation, compared with fibroblasts lacking p53 alone. This defect co uld be restored by reconstitution of c-Abl expression. Taken together, thes e results indicate that the ATM phenotype cannot be explained solely by los s of c-Abl and p53 and that c-Abl contributes to enhanced proliferation of p53-deficient cells. Inhibition of c-Abl function may be a therapeutic stra tegy to target p53-deficient cells selectively.