Related Experiment Video
Updated: Oct 21, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Inhibition of nonsense-mediated decay rescues p53β/γ isoform expression and activates the p53 pathway in
Jayanthi P Gudikote1, Tina Cascone1, Alissa Poteete1
1Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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.
Insights
Inhibiting nonsense-mediated decay (NMD) reactivates the tumor suppressor p53 in certain cancers by upregulating p53β and p53γ isoforms. This strategy shows promise for treating p53-deficient tumors, including non-small cell lung cancer and glioblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- p53 tumor suppressor inactivation is nearly universal in cancer, necessitating p53-reactivation strategies.
- Loss of p53 function occurs via MDM2 overexpression or TP53 mutations, with limited current therapeutic options.
- Alternative p53 isoforms (p53β, p53γ) are less susceptible to MDM2 degradation but vulnerable to nonsense-mediated decay (NMD).
Purpose of the Study:
- To investigate the therapeutic potential of NMD inhibition for restoring p53 function in cancer cells with p53 inactivation.
- To evaluate the impact of NMD inhibition on p53 isoforms and downstream tumor suppressive activities.
Main Methods:
- Utilized non-small cell lung cancer and glioblastoma cell line models.
- Assessed the effect of NMD inhibition on p53β and p53γ isoform levels.
- Evaluated tumor suppressive activities (apoptosis, cell viability, radiosensitivity) and tumor growth in vivo.
Main Results:
- NMD inhibition significantly upregulated p53β and p53γ isoforms in cancer cells with MDM2 overexpression or TP53 mutations downstream of exon 9.
- NMD inhibition restored p53 pathway activation, inducing apoptosis, reducing cell viability, and enhancing radiosensitivity.
- NMD inhibition demonstrated tumor growth inhibition in a xenograft model.
Conclusions:
- NMD inhibition is a novel therapeutic strategy for restoring p53 function in specific p53-deficient cancers.
- This approach is effective in tumors with MDM2 overexpression or TP53 mutations downstream of exon 9, representing a significant patient subgroup.
- Targeting NMD offers a promising avenue for cancer therapy by reactivating the p53 pathway.
Related Concept Videos
02:23Abnormal Proliferation
02:37DNA Damage can Stall the Cell Cycle
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:27Nonsense-mediated mRNA Decay
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
01:23Negative Regulator Molecules
01:31The Intrinsic Apoptotic Pathway