Original Article

Oncogene (2010) 29, 1260–1269; doi:10.1038/onc.2009.423; published online 23 November 2009

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

S M Post1, A Quintás-Cardama1,2, T Terzian1, C Smith3, C M Eischen4 and G Lozano1

  1. 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  3. 3Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  4. 4Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA

Correspondence: Professor Dr G Lozano, Department of Genetics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1010, Houston, TX 77030, USA. E-mail: gglozano@mdanderson.org

Received 6 May 2009; Revised 17 August 2009; Accepted 25 September 2009; Published online 23 November 2009.

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Abstract

The effect of p53-dependent cell-cycle arrest and senescence on Eμ-myc-induced B-cell lymphoma development remains controversial. To address this question, we crossed Eμ-myc mice with the p53515C 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, Eμ-myc mice that harbor two p53515C alleles are completely defective for p53-dependent apoptosis. Both Eμ-myc::p53515C/515C and Eμ-myc::p53515C/+ mice survive significantly longer than Eμ-myc::p53+/ mice, indicating the importance of the p53-dependent non-apoptotic pathways in B-cell lymphomagenesis. In addition, the p53515C allele is deleted in several Eμ-myc::p53515C/+ lymphomas, further emphasizing the functionality of p53R172P in tumor inhibition. Lymphomas from both Eμ-myc::p53515C/515C and Eμ-myc::p53515C/+ mice retain the ability to upregulate p21, resulting in cellular senescence. Senescence-associated β-galactosidase (SA β-gal) activity was observed in lymphomas from Eμ-myc::p53+/+, Eμ-myc::p53515C/515C and Eμ-myc::p53515C /+ mice but not in lymphomas isolated from Eμ-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.

Keywords:

p53, apoptosis, senescence, lymphoma, mouse model

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