p53-dependent senescence delays Emu-myc-induced B-cell lymphomagenesis.

Post SM, Quintás-Cardama A, Terzian T, Smith C, Eischen CM, Lozano G
Oncogene. 2010 29 (9): 1260-9

PMID: 19935700 · PMCID: PMC2903442 · DOI:10.1038/onc.2009.423

The effect of p53-dependent cell-cycle arrest and senescence on Emu-myc-induced B-cell lymphoma development remains controversial. To address this question, we crossed Emu-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, Emu-myc mice that harbor two p53(515C) alleles are completely defective for p53-dependent apoptosis. Both Emu-myc::p53(515C/515C) and Emu-myc::p53(515C/+) mice survive significantly longer than Emu-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 Emu-myc::p53(515C/+) lymphomas, further emphasizing the functionality of p53R172P in tumor inhibition. Lymphomas from both Emu-myc::p53(515C/515C) and Emu-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 Emu-myc::p53(+/+), Emu-myc::p53(515C/515C) and Emu-myc::p53(515C /+) mice but not in lymphomas isolated from Emu-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.

MeSH Terms (13)

Aging Animals Apoptosis B-Lymphocytes beta-Galactosidase Cyclin-Dependent Kinase Inhibitor p16 Dromaiidae Genes, p53 Lymphoma Lymphoma, B-Cell Mice Proto-Oncogene Proteins c-myc Tumor Suppressor Protein p53

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