Suppression of stress granule formation is a vulnerability imposed by mutant p53
Abstract Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53null) HCC, unlike other cancer t...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57539-6 |
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| author | Elizabeth Thoenen Atul Ranjan Alejandro Parrales Shigeto Nishikawa Dan A. Dixon Sugako Oka Tomoo Iwakuma |
| author_facet | Elizabeth Thoenen Atul Ranjan Alejandro Parrales Shigeto Nishikawa Dan A. Dixon Sugako Oka Tomoo Iwakuma |
| author_sort | Elizabeth Thoenen |
| collection | DOAJ |
| description | Abstract Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53null) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 domain-binding protein 1 (G3BP1), contributing to increased sensitivity of SG-competent cells and xenografts to ER stress inducers including SOR. Our study identifies a unique vulnerability imposed by mutp53, suggesting mutp53 as a biomarker for ER stress-inducing agents and highlighting the importance of SG inhibition for cancer treatment. |
| format | Article |
| id | doaj-art-4d327c8add6349e986d7775d0a39c5db |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4d327c8add6349e986d7775d0a39c5db2025-08-20T02:56:20ZengNature PortfolioNature Communications2041-17232025-03-0116111710.1038/s41467-025-57539-6Suppression of stress granule formation is a vulnerability imposed by mutant p53Elizabeth Thoenen0Atul Ranjan1Alejandro Parrales2Shigeto Nishikawa3Dan A. Dixon4Sugako Oka5Tomoo Iwakuma6Department of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteDepartment of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteDepartment of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteDepartment of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteDepartment of Biochemistry and Molecular Biology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical SciencesFaculty of Medical Science, Kyushu UniversityDepartment of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research InstituteAbstract Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53null) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 domain-binding protein 1 (G3BP1), contributing to increased sensitivity of SG-competent cells and xenografts to ER stress inducers including SOR. Our study identifies a unique vulnerability imposed by mutp53, suggesting mutp53 as a biomarker for ER stress-inducing agents and highlighting the importance of SG inhibition for cancer treatment.https://doi.org/10.1038/s41467-025-57539-6 |
| spellingShingle | Elizabeth Thoenen Atul Ranjan Alejandro Parrales Shigeto Nishikawa Dan A. Dixon Sugako Oka Tomoo Iwakuma Suppression of stress granule formation is a vulnerability imposed by mutant p53 Nature Communications |
| title | Suppression of stress granule formation is a vulnerability imposed by mutant p53 |
| title_full | Suppression of stress granule formation is a vulnerability imposed by mutant p53 |
| title_fullStr | Suppression of stress granule formation is a vulnerability imposed by mutant p53 |
| title_full_unstemmed | Suppression of stress granule formation is a vulnerability imposed by mutant p53 |
| title_short | Suppression of stress granule formation is a vulnerability imposed by mutant p53 |
| title_sort | suppression of stress granule formation is a vulnerability imposed by mutant p53 |
| url | https://doi.org/10.1038/s41467-025-57539-6 |
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