p53-dependent senescence delays Eμ-myc-induced B-cell lymphomagenesis

The effect of p53-dependent cell-cycle arrest and senescence on E mu-myc-induced B-cell lymphoma development remains controversial. To address this question, we crossed E mu-myc mice with the p53(515C) mutant mouse, encoding the mutant p53R172P protein that retains the ability to activate the cell-cycle inhibitor and senescence activator p21. Importantly, this mutant lacks the ability to activate p53-dependent apoptotic genes. Hence, E mu-myc mice that harbor two p53(515C) alleles are completely defective for p53-dependent apoptosis. Both E mu-myc::p53(515C/515C) and E mu-myc::p53(515C/+) mice survive significantly longer than E mu-myc::p53(+/-) mice, indicating the importance of the p53-dependent non-apoptotic pathways in B-cell lymphomagenesis. In addition, the p53(515C) allele is deleted in several E mu-myc::p53(515C/+) lymphomas, further emphasizing the functionality of p53R172P in tumor inhibition. Lymphomas from both E mu-myc:: p53(515C/515C) and E mu-myc::p53(515C/+) mice retain the ability to upregulate p21, resulting in cellular senescence. Senescence-associated beta-galactosidase (SA beta-gal) activity was observed in lymphomas from E mu-myc::p53(+/+), E mu-myc::p53(515C/515C) and E mu-myc::p53(515C /+) mice but not in lymphomas isolated from E mu-myc::p53(+/-) mice. Thus, in the absence of p53-dependent apoptosis, the ability of p53R172P to induce senescence leads to a significant delay in B-cell lymphoma development. Oncogene (2010) 29, 1260-1269; doi:10.1038/onc.2009.423; published online 23 November 2009