EVIDENCE THAT P53 AND BCL-2 ARE REGULATORS OF A COMMON CELL-DEATH PATHWAY IMPORTANT FOR IN-VIVO LYMPHOMAGENESIS

Multistep lymphomagenesis involves the deregulation of oncogenes and i nactivation of tumor suppressor genes resulting in altered rates of pr oliferation as well as apoptotic cell death in tumor cells. The contri bution of bcl-2 and p53 to the regulation of cell death during lymphom agenesis is assessed using bcl-2-1g, p53 'knockout' (p53 KO), and p53 KO/bcl-2 hybrid mice. PCR-SSCP and DNA sequence analysis demonstrated that p53 somatic mutations are uncommon in lymphomas arising in bcl-2- Ig transgenic mice. Reduction in tumor latency was not observed in p53 KO/bcl-2 hybrid mice compared to p53 KO mice. Furthermore, overexpres sed bcl-2 suppressed wild-type p53 associated apoptosis following gamm a-radiation. These findings indicate that bcl-2 and p53 serve a suppre ssor and effector function, respectively, of a common cell death pathw ay. These findings also suggest that p53 somatic mutations provide no selective advantage during in vivo multistep lymphomagenesis in the co ntext of bcl-2 gene deregulation.