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MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation

Oncogene volume 36, pages 1760–1769 (2017)Cite this article

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Abstract

Retinoblastomas can arise from cone photoreceptor precursors in response to the loss of pRB function. Cone precursor-specific circuitry cooperates with pRB loss to initiate this process and subsequently contributes to the malignancy. Intrinsic high-level MDM2 expression is a key component of the cone precursor circuitry and is thought to inactivate p53-mediated tumor surveillance, which could otherwise be induced in response to pRB loss. However, the MDM2-related MDM4 has also been proposed to abrogate p53-mediated tumor surveillance in the absence of detectable MDM2 in retinoblastoma cells, bringing into question the importance of high-level MDM2 versus MDM4 expression. Here we report that high-level MDM2 but not MDM4 has a consistent critical role in retinoblastoma cell proliferation in vitro, as well as in orthotopic xenografts. Reduction of either MDM2 or MDM4 weakly induced p53, yet reduction of MDM2 but not MDM4 severely impaired proliferation and survival through a p53-independent mechanism. Specifically, MDM2 upregulated the mRNA expression and translation of another component of the cone circuitry, MYCN, in retinoblastoma cells. Moreover, MYCN was essential to retinoblastoma cell growth and tumor formation, and ectopic MYCN partially reversed the effects of MDM2 depletion, indicating that MYCN is an important MDM2 target. These findings indicate that high-level MDM2 expression is needed in order to perform a critical p53-independent function and may obviate the need for genomic alterations to the p53 pathway during retinoblastoma tumorigenesis.

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Acknowledgements

D–L Qi and D Cobrinik designed the study. D–L Qi conducted all the experiments. D–L Qi and D Cobrinik wrote the manuscript. We thank Xiaoliang Leon Xu for early passage retinoblastoma cell preparations, Narine Harutyunyan and Jennifer Aparicio for CHLAVC-RB43, Pat Reynolds and A Linn Murphree for CHLA-RB215 cells, and the Saban Research Institute Research Imaging Core for assistance. This study was supported by NIH grants 1R01CA137124 and P30CA014089, by a Saban Research Institute Research Career Development Fellowship to D–L Qi, by Research to Prevent Blindness (New York, New York), by the Larry & Celia Moh Foundation and by the charitable support of the Nautica Malibu Triathlon event produced by MESP, Inc.

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Authors and Affiliations

  1. Division of Ophthalmology, Department of Surgery, The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    D-L Qi & D Cobrinik

  2. The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    D-L Qi & D Cobrinik

  3. USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    D Cobrinik

  4. Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    D Cobrinik

  5. Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    D Cobrinik

  6. Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    D Cobrinik

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Correspondence to D Cobrinik.

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Qi, DL., Cobrinik, D. MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation. Oncogene 36, 1760–1769 (2017). https://doi.org/10.1038/onc.2016.350

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