ArticleProceedings of the National Academy of Sciences of the United States of America2014
Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 45 citations in OpenAlex.
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- STK39 inhibits antiviral immune response by inhibiting DCAF1-mediated PP2A degradation.Acta pharmaceutica Sinica. B · 2025Article
- Advances in Synthetic Lethality in Potential Oncology Therapeutic Approaches.Current topics in medicinal chemistry · 2025Review
- TSG101 depletion dysregulates mitochondria and PML NBs, triggering MAD2-overexpressing interphase cell death (MOID) through AIFM1-PML-DAXX pathway.Cell death & disease · 2024Article
- Unleashing the Power of Synthetic Lethality: Augmenting Treatment Efficacy through Synergistic Integration with Chemotherapy Drugs.Pharmaceutics · 2023Review
- Mapping Synthetic Dosage Lethal Genetic Interactions in Saccharomyces cerevisiae.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Development of synthetic lethality in cancer: molecular and cellular classification.Signal transduction and targeted therapy · 2020Review
- Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation.Journal of hematology & oncology · 2020Review
- Genomics-guided pre-clinical development of cancer therapies.Nature cancer · 2020Review
- Human artificial chromosome (HAC) for measuring chromosome instability (CIN) and identification of genes required for proper chromosome transmission.Experimental cell research · 2020Review
- Aneuploidy: Cancer strength or vulnerability?International journal of cancer · 2019Review
- Targeting PP2A in cancer: Combination therapies.Biochimica et biophysica acta. Molecular cell research · 2019Review
- How Surrogate and Chemical Genetics in Model Organisms Can Suggest Therapies for Human Genetic Diseases.Genetics · 2018Review
- Recent Advances in Herbal Medicines for Digestive System Malignancies.Frontiers in pharmacology · 2018Review
- Synthetic lethality and cancer.Nature reviews. Genetics · 2017Review
- Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit.Cell reports · 2017Article
- Pathological significance of MAD2L1 in breast cancer: an immunohistochemical study and meta analysis.International journal of clinical and experimental pathology · 2017Article
- Therapeutic relevance of the protein phosphatase 2A in cancer.Oncotarget · 2016Article
- Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Regulation of AURORA B function by mitotic checkpoint protein MAD2.Cell cycle (Georgetown, Tex.) · 2016Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The spindle checkpoint is essential to ensure proper chromosome segregation and thereby maintain genomic stability. Mitotic arrest deficiency 2 (Mad2), a critical component of the spindle checkpoint, is overexpressed in many cancer cells. Thus, we hypothesized that Mad2 overexpression could specifically make cancer cells susceptible to death by inducing a synthetic dosage lethality defect. Because the spindle checkpoint pathway is highly conserved between yeast and humans, we performed a synthetic genetic array analysis in yeast, which revealed that Mad2 overexpression induced lethality in 13 gene deletions. Among the human homologs of candidate genes, knockdown of PPP2R1A, a gene encoding a constant regulatory subunit of protein phosphatase 2, significantly inhibited the growth of Mad2-overexpressing tumor cells. PPP2R1A inhibition induced Mad2 phosphorylation and suppressed Mad2 protein levels. Depletion of PPP2R1A inhibited colony formation of Mad2-overexpressing HeLa cells but not of unphosphorylated Mad2 mutant-overexpressing cells, suggesting that the lethality induced by PP2A depletion in Mad2-overexpressing cells is dependent on Mad2 phosphorylation. Also, the PP2A inhibitor cantharidin induced Mad2 phosphorylation and inhibited the growth of Mad2-overexpressing cancer cells. Aurora B knockdown inhibited Mad2 phosphorylation in mitosis, resulting in the blocking of PPP2R1A inhibition-induced cell death. Taken together, our results strongly suggest that PP2A is a good therapeutic target in Mad2-overexpressing tumors.
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