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Inhibition of nonsense-mediated decay rescues functional p53β/γ isoforms in MDM2-amplified cancers

By Jayanthi P Gudikote, Tina Cascone, Alissa Poteete, Piyada Sitthideatphaiboon, Qiuyu Wu, Naoto Morikawa, Fahao Zhang, Shaohua Peng, Pan Tong, Lerong Li, Li Shen, Monique Nilsson, Phillip Jones, Erik P Sulman, Jing Wang, Jean-Christophe Bourdon, Faye M. Johnson, John V Heymach

Posted 07 Apr 2020
bioRxiv DOI: 10.1101/2020.04.06.026955

Common mechanisms for p53 loss in cancer include expression of MDM2 or the human papilloma virus (HPV)-encoded E6 protein which both mediate degradation of wild-type (WT) p53 (p53α). Here, we show that two alternatively-spliced, functional, truncated isoforms of p53 (p53β and p53γ, containing exons 1-9 of the p53 gene) can be markedly upregulated by pharmacologic or genetic inhibition of nonsense mediated decay (NMD), a regulator of aberrant mRNA stability. These isoforms lack the MDM2 binding domain and hence have reduced susceptibility to MDM2-mediated degradation. In MDM2-overexpressing cells bearing wild-type TP53 gene, NMD blockade increased p53β/γ expression and p53 pathway activation, enhanced radiosensitivity, and inhibited tumor growth. A similar pattern was observed in HPV+ cancer cells and in cancer cells with p53 mutations downstream of exon 9. These results identify a novel therapeutic strategy for restoration of p53 function in tumors rendered p53 deficient through MDM2 overexpression, HPV infection, or certain p53 mutations.

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