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

Oncogene volume 29, pages 1260–1269 (2010)Cite this article

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.

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Acknowledgements

We thank Dr Tomoo Iwakuma, Arlette Audiffred and Kristina Castro for helpful discussions and technical assistance, and Dr Clifton Stephens for pathological analysis. We thank Drs Jim Jackson and Vinod Pant for review of this paper. Veterinary support and DNA sequencing core facilities were supported by NCI Cancer Center Support Grant CA16672. SMP is supported by a Ruth L Kirschstein NRSA fellowship F32CA119616 and is a recipient of the Dowdy P Hawn postdoctoral fellowship. This study was supported by NIH Grant CA82577 (to GL).

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Authors and Affiliations

  1. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S M Post, A Quintás-Cardama, T Terzian & G Lozano

  2. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Quintás-Cardama

  3. Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Smith

  4. Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA

    C M Eischen

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  1. S M Post
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  2. A Quintás-Cardama
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  4. C Smith
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  5. C M Eischen
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  6. G Lozano
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Correspondence to G Lozano.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Post, S., Quintás-Cardama, A., Terzian, T. et al. p53-dependent senescence delays Eμ-myc-induced B-cell lymphomagenesis. Oncogene 29, 1260–1269 (2010). https://doi.org/10.1038/onc.2009.423

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