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

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 (p53β and p53, 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 wildtype TP53 gene, NMD blockade increased p53β/ 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.Key words. HPV-associated cancers/MDM2 amplified cancers/NMD inhibition/p53β and p53 isoforms/Restoration of p53 functions/Therapeutic strategy for p53 deficient cancers

Tau‐induced deficits in nonsense‐mediated mRNA decay contribute to neurodegeneration

“…We next asked if tau-induced deficits in NMD are pharmacologically targetable. Although an increasing number of preclinical drugs that inhibit NMD are in development for the treatment of cancer and human genetic disorders caused by a single base-pair mutation, [108][109][110][111] NMD-activating drugs are less common. We first determined if tranilast, a previously identified NMD activator in Drosophila, 60 effectively activates NMD in tauopathy.…”

Genomic instability in patients with sex determination defects and germ cell cancer

“…5b, f). C-terminus modifications can also influence TP53 protein stability (46), while we detected no variability in sequences of exons 10 and 11 in Swyer samples, even with GCT (Fig. S4).…”

Transcriptome-wide analysis of primary human endothelial cell responses to 1 hour of protein translation inhibition identify nonsense mediated decay targets and a non-codingSLC11A2exon as an acute biomarker

“…[17] NMD inhibition has also been proposed for states where tumors use NMD to downregulate tumor suppressor genes. [18,19] Nevertheless, since inhibition of nonsense mediated decay is a nonspecific strategy, it can potentially affect any transcripts harboring a PTC. Further, while PTC+ mRNAs are default targets of NMD, recent findings indicate that mRNAs with features other than PTCs are also major contributor to biology consequences when NMD is inhibited.…”