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Disruption of the RP-MDM2-p53 pathway accelerates APC loss-induced colorectal tumorigenesis

Oncogene volume 36, pages 1374–1383 (2017)Cite this article

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Abstract

Inactivation of the adenomatous polyposis coli (APC) tumor suppressor is frequently found in colorectal cancer. Loss of APC function results in deregulation of the Wnt/β-catenin signaling pathway causing overexpression of the c-MYC oncogene. In lymphoma, both p19ARF and ribosomal proteins RPL11 and RPL5 respond to c-MYC activation to induce p53. Their role in c-MYC-driven colorectal carcinogenesis is unclear, as p19ARF deletion does not accelerate APC loss-triggered intestinal tumorigenesis. To determine the contribution of the ribosomal protein (RP)-murine double minute 2 (MDM2)-p53 pathway to APC loss-induced tumorigenesis, we crossed mice bearing MDM2C305F mutation, which disrupts RPL11- and RPL5-MDM2 binding, with Apcmin/+ mice, which are prone to intestinal tumor formation. Interestingly, loss of RP-MDM2 binding significantly accelerated colorectal tumor formation while having no discernable effect on small intestinal tumor formation. Mechanistically, APC loss leads to overexpression of c-MYC, RPL11 and RPL5 in mouse colonic tumor cells irrespective of MDM2C305F mutation. However, notable p53 stabilization and activation were observed only in Apcmin/+;Mdm2+/+ but not Apcmin/+;Mdm2C305F/C305F colon tumors. These data establish that the RP-MDM2-p53 pathway, in contrast to the p19ARF-MDM2-p53 pathway, is a critical mediator of colorectal tumorigenesis following APC loss.

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Acknowledgements

This research was supported by grants from the National Institutes of Health (CA127770, CA 100302 and CA167637) and Natural Science Foundation of China (NSFC) to YZ, and the National Institute of General Medical Sciences (5T32 GM007092) to NRT.

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Authors and Affiliations

  1. Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    S Liu, N R Tackmann, J Yang & Y Zhang

  2. Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    N R Tackmann & Y Zhang

  3. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China

    J Yang & Y Zhang

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Correspondence to Y Zhang.

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Liu, S., Tackmann, N., Yang, J. et al. Disruption of the RP-MDM2-p53 pathway accelerates APC loss-induced colorectal tumorigenesis. Oncogene 36, 1374–1383 (2017). https://doi.org/10.1038/onc.2016.301

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