Abstract 3691: MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation

Abstract

Abstract Retinoblastomas can arise from cone photoreceptor precursors in response to the loss of pRB function. Some aspects of cone precursor-specific circuitry cooperate with pRB loss to initiate this process and subsequently continue to contribute to the malignancy. Intrinsic high level MDM2 expression is a key component of this circuitry and is thought to inactivate p53-mediated tumor surveillance that could otherwise be induced by aberrant cell cycle entry. However, the MDM2-related MDM4 has also been proposed to abrogate p53-mediated tumor surveillance in the absence of detectable MDM2. Here we report that high-level MDM2 but not MDM4 has a consistent, critical role in retinoblastoma cell proliferation. Reduction of MDM2 and MDM4 only weakly induced p53, yet reduction of MDM2 but not MDM4 severely impaired proliferation and survival through a p53-independent mechanism. Specifically, MDM2 up-regulated the translation of another component of the cone circuitry, MYCN, in retinoblastoma cells. 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 in retinoblastoma cells. Citation Format: Donglai Qi, David E. Cobrinik. MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3691.