Mice lacking both p57 and p53 develop lymphoma. (A) Gross appearance of the thymus of Lck-Cre/p57^[+]/+, Lck-Cre/p57^[+]/+/p53^−/−, Lck-Cre/p57^[+]/F, and Lck-Cre/p57^[+]/F/p53^−/− mice at 8 weeks of age. Scale bar, 2 mm. (B-C) Representative flow cytometric analysis of CD4 vs CD8 on thymocytes (B) as well as of TCRβ on electronically gated CD8 SP cells (C) from Lck-Cre/p57^[+]/+ and Lck-Cre/p57^[+]/F/p53^−/− mice shown in panel A. Percentages of each fraction are indicated. (D) Kaplan-Meier plot for overall survival of mice of the indicated genotypes. (E) Model for the role of p57 in T cell differentiation and prevention of lymphomagenesis. Differentiation of pre-T cells depends on a balance between p53 activity and pre-TCR signaling. Ablation of p57 results in hyperactivation of p53 and thereby induces apoptosis in and blocks the development of immature T cells. Additional ablation of E2F1 results in a partial rescue of the phenotypes associated with p57 deficiency. The simultaneous ablation of p57 and p53 results in aberrant expansion of immature T cells, eventually leading to the development of fatal thymic lymphoma. See Discussion for further details.