Potential synergism of Bim with p53 in mice with Myc‑induced lymphoma in a mouse lymphoma model.

We report that Bim has an apoptotic function through Bax/mitochondrial apoptosis signaling in the p53-independent mode, which is somewhat additive to the effects of p53. Bim-deficient mouse embryonic fibroblast (MEF) cells were resistant to the apoptotic effects of Myc, while loss of Bim accelerated lymphoma development. Furthermore, Bim was overexpressed at the same frequency in Myc-initiated lymphomas, irrespective of p53 status, suggesting that Bim resides in a pathway separate from p53. Loss of Bim further augmented resistance to apoptosis in p53-/- MEFs. Mice with p53 knockdown exhibited exacerbated malignancies in the absence of Bim. The combined loss of these proteins promoted more severe spontaneous tumorigenesis. Thus, Myc-induced apoptotic signals through Bim and p53 must bifurcate to activate Bax, suggesting that the activation of Bim and p53 significantly contribute to apoptosis. Our results, therefore, establish that p53 and Bim are effective key initiators of apoptosis in lymphoma cells, particularly when combined.