The p53–Bcl-2 connection

The tumor suppressor p53 and the proto-oncogene Bcl-2 were two of the earliest identified cancer genes. Mutant p53 proteins were first discovered in transformed murine cell lines,^{1, 2} whereas Bcl-2 translocations were first identified in human follicular lymphoma.^{3, 4, 5} Despite this shared cancer relevance, they were initially thought to have little else in common. p53 was proposed to activate cell cycle checkpoints,⁶ whereas Bcl-2 was shown to inhibit cell death. Additionally, Bcl-2 overexpression was found exclusively in hematopoietic cancers, whereas p53 mutations were primarily found in solid tumors. However, the last 15 years have witnessed the emergence of strong genetic and biochemical ties between these two proteins, and it has become increasingly evident that signaling between p53 and Bcl-2 is of fundamental importance to cancer biology. This News and Commentary will focus on the pathways connecting p53 with Bcl-2 and the deregulation of this signaling network during tumor development.

p53 is a sequence-specific transcription factor that is activated by diverse forms of cellular stress.⁷ Early studies of p53 focused on the ability of tumor-derived p53 mutants to promote cell growth and transformation.^{8, 9, 10} Subsequently, p53 was characterized as an essential mediator of cell cycle arrest in response to diverse cellular stresses.^{11, 12} The first suggestion that p53 could promote apoptosis came more than 10 years after its discovery from experiments in which p53 was introduced into a p53-deficient leukemia cell line. These experiments showed that enforced p53 expression could induce cell death in cells deprived of prosurvival cytokines.¹³ Subsequently, work in p53 knockout mice demonstrated that p53 activity was essential for radiation-induced death in thymocytes and chemotherapy-induced apoptosis in fibroblasts expressing deregulated oncogenes.^{14, 15, 16}

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