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Inhibition of nonsense-mediated decay rescues p53β/γ isoform expression and activates the p53 pathway in MDM2-overexpressing and select p53-mutant cancers
- Source :
- The Journal of Biological Chemistry
- Publication Year :
- 2021
- Publisher :
- American Society for Biochemistry and Molecular Biology, 2021.
-
Abstract
- Inactivation of p53 is present in almost every tumor, and hence, p53-reactivation strategies are an important aspect of cancer therapy. Common mechanisms for p53 loss in cancer include expression of p53-negative regulators such as MDM2, which mediate the degradation of wildtype p53 (p53α), and inactivating mutations in the TP53 gene. Currently, approaches to overcome p53 deficiency in these cancers are limited. Here, using non–small cell lung cancer and glioblastoma multiforme cell line models, we show that two alternatively spliced, functional truncated isoforms of p53 (p53β and p53γ, comprising exons 1 to 9β or 9γ, respectively) and that lack the C-terminal MDM2-binding domain have markedly reduced susceptibility to MDM2-mediated degradation but are highly susceptible to nonsense-mediated decay (NMD), a regulator of aberrant mRNA stability. In cancer cells harboring MDM2 overexpression or TP53 mutations downstream of exon 9, NMD inhibition markedly upregulates p53β and p53γ and restores activation of the p53 pathway. Consistent with p53 pathway activation, NMD inhibition induces tumor suppressive activities such as apoptosis, reduced cell viability, and enhanced tumor radiosensitivity, in a relatively p53-dependent manner. In addition, NMD inhibition also inhibits tumor growth in a MDM2-overexpressing xenograft tumor model. These results identify NMD inhibition as a novel therapeutic strategy for restoration of p53 function in p53-deficient tumors bearing MDM2 overexpression or p53 mutations downstream of exon 9, subgroups that comprise approximately 6% of all cancers.
- Subjects :
- p53
Nonsense-mediated decay
DMSO, dimethyl sulfoxide
Biochemistry
Exon
alternative splicing
Mice
mRNA decay
RNA degradation
MDM2
NSCLC, non–small cell lung cancer
medicine
Animals
Humans
Protein Isoforms
Molecular Biology
biology
Chemistry
NMD, nonsense-mediated decay
Alternative splicing
Wild type
Cancer
PTC, premature termination codon
Proto-Oncogene Proteins c-mdm2
Cell Biology
GBM, glioblastoma multiforme
medicine.disease
Nonsense Mediated mRNA Decay
Gene Expression Regulation, Neoplastic
Apoptosis
A549 Cells
Cancer cell
Mutation
biology.protein
Cancer research
Mdm2
cancer therapy
IR, ionizing radiation
targeting NMD
p53β/γ restoration
Tumor Suppressor Protein p53
NMDi, NMD inhibitor
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 1083351X and 00219258
- Volume :
- 297
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- The Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....141972075328430857ff8891a8eb428e