Apr 7, 2020

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

BioRxiv : the Preprint Server for Biology
J. P. GudikoteJohn Heymach

Abstract

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 (p53). Here, we show that two alternatively-spliced, functional, truncated isoforms of p53 (p53{beta} and p53{gamma}, 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 p53{beta}/{gamma} 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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Mentioned in this Paper

Single-Cell Analysis
Biological Markers
SET
Meta Analysis (Statistical Procedure)
Pluripotent Stem Cells
High Throughput Screening
Science of Morphology
Candidate Disease Gene
SMG1
Human Induced Pluripotent Stem Cells

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