p53-dependent senescence delays Emu-myc-induced B-cell lymphomagenesis.
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.
Post
S M
SM
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Quintás-Cardama
A
A
Terzian
T
T
Smith
C
C
Eischen
C M
CM
Lozano
G
G
D000375:Aging / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000494:pharmacology; D020312:Dromaiidae; D016158:Genes, p53 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D008223:Lymphoma / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology*; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000494:pharmacology; D001616:beta-Galactosidase / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase