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A deficiency in Mdm2 binding protein inhibits Myc-induced B-cell proliferation and lymphomagenesis

Oncogene volume 29, pages 3287–3296 (2010)Cite this article

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Abstract

Mdm2 binding protein (MTBP) has been implicated in cell-cycle arrest and the Mdm2/p53 tumor suppressor pathway through its interaction with Mdm2. To determine the function of MTBP in tumorigenesis and its potential role in the Mdm2/p53 pathway, we crossed Mtbp-deficient mice to Eμ-myc transgenic mice, in which overexpression of the oncogene c-Myc induces B-cell lymphomas primarily through inactivation of the Mdm2/p53 pathway. We report that Myc-induced B-cell lymphoma development in Mtbp heterozygous mice was profoundly delayed. Surprisingly, reduced levels of Mtbp did not lead to an increase in B-cell apoptosis or affect Mdm2. Instead, an Mtbp deficiency inhibited Myc-induced proliferation and the upregulation of Myc target genes necessary for cell growth. Consistent with a role in proliferation, Mtbp expression was induced by Myc and other factors that promote cell-cycle progression and was elevated in lymphomas from humans and mice. Therefore, Mtbp functioned independent of Mdm2 and was a limiting factor for the proliferative and transforming functions of Myc. Thus, Mtbp is a previously unrecognized regulator of Myc-induced tumorigenesis.

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Acknowledgements

We thank Dr Silvia Plaza, Brandon Metge, Jane Kennedy, and Dr Chris Carbone for expert technical assistance, Dr Xavier Graña for assistance with the adenoviruses and the H1299 cell-cycle studies, and Dr William Dupont and Dale Plummer for Kaplan–Meier analysis. We also thank the following individuals for providing recombinant adenoviruses: Dr Joseph Nevins (Duke University) E2F1 and c-Myc, Dr Juan Fueyo (MD Anderson Cancer Center) p16, Dr Wafik El-Deiry (University of Pennsylvania) p21, and Dr Ruiz-Lozano (Burnham Institute) GFP. This work was supported by NCI Grants R01CA098139, R01CA117935 and P30CA068485 (CME); the Leukemia & Lymphoma Society (CME) and P01CA095569 (DH and JG).

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Author notes

  1. J Odvody, T Vincent and M P Arrate: These authors contributed equally to this work.

Authors and Affiliations

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

    J Odvody, T Vincent, M P Arrate, B Grieb & C M Eischen

  2. Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA

    S Wang & D S Haines

  3. Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA

    J Garriga & D S Haines

  4. Department of Molecular Genetics Section of Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Lozano

  5. Department of Genetics, Louisiana State University Health Science Center, New Orleans, LA, USA

    T Iwakuma

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  1. J Odvody
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  2. T Vincent
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  7. G Lozano
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  8. T Iwakuma
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  9. D S Haines
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  10. C M Eischen
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Correspondence to C M Eischen.

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Odvody, J., Vincent, T., Arrate, M. et al. A deficiency in Mdm2 binding protein inhibits Myc-induced B-cell proliferation and lymphomagenesis. Oncogene 29, 3287–3296 (2010). https://doi.org/10.1038/onc.2010.82

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