Identification of Small Molecules that Modulate Mutant p53 Condensation
Summary: Structural mutants of p53 induce global p53 protein destabilization and misfolding, followed by p53 protein aggregation. First evidence indicates that p53 can be part of protein condensates and that p53 aggregation potentially transitions through a condensate-like state. We show condensate-...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220307094 |
| _version_ | 1828902229812183040 |
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| author | Clara Lemos Luise Schulze Joerg Weiske Hanna Meyer Nico Braeuer Naomi Barak Uwe Eberspächer Nicolas Werbeck Carlo Stresemann Martin Lange Ralf Lesche Nina Zablowsky Katrin Juenemann Atanas Kamburov Laura Martina Luh Thomas Markus Leissing Jeremie Mortier Michael Steckel Holger Steuber Knut Eis Ashley Eheim Patrick Steigemann |
| author_facet | Clara Lemos Luise Schulze Joerg Weiske Hanna Meyer Nico Braeuer Naomi Barak Uwe Eberspächer Nicolas Werbeck Carlo Stresemann Martin Lange Ralf Lesche Nina Zablowsky Katrin Juenemann Atanas Kamburov Laura Martina Luh Thomas Markus Leissing Jeremie Mortier Michael Steckel Holger Steuber Knut Eis Ashley Eheim Patrick Steigemann |
| author_sort | Clara Lemos |
| collection | DOAJ |
| description | Summary: Structural mutants of p53 induce global p53 protein destabilization and misfolding, followed by p53 protein aggregation. First evidence indicates that p53 can be part of protein condensates and that p53 aggregation potentially transitions through a condensate-like state. We show condensate-like states of fluorescently labeled structural mutant p53 in the nucleus of living cancer cells. We furthermore identified small molecule compounds that interact with the p53 protein and lead to dissolution of p53 structural mutant condensates. The same compounds lead to condensation of a fluorescently tagged p53 DNA-binding mutant, indicating that the identified compounds differentially alter p53 condensation behavior depending on the type of p53 mutation.In contrast to p53 aggregation inhibitors, these compounds are active on p53 condensates and do not lead to mutant p53 reactivation. Taken together our study provides evidence for structural mutant p53 condensation in living cells and tools to modulate this process. |
| first_indexed | 2024-12-13T16:13:07Z |
| format | Article |
| id | doaj.art-a212af021eff409c84704cd1ec1f0308 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-13T16:13:07Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-a212af021eff409c84704cd1ec1f03082022-12-21T23:38:53ZengElsevieriScience2589-00422020-09-01239101517Identification of Small Molecules that Modulate Mutant p53 CondensationClara Lemos0Luise Schulze1Joerg Weiske2Hanna Meyer3Nico Braeuer4Naomi Barak5Uwe Eberspächer6Nicolas Werbeck7Carlo Stresemann8Martin Lange9Ralf Lesche10Nina Zablowsky11Katrin Juenemann12Atanas Kamburov13Laura Martina Luh14Thomas Markus Leissing15Jeremie Mortier16Michael Steckel17Holger Steuber18Knut Eis19Ashley Eheim20Patrick Steigemann21Bayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, Germany; Corresponding authorBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, GermanyBayer AG Research and Development, Pharmaceuticals, Müllerstr. 178, 13342 Berlin, Germany; Corresponding authorSummary: Structural mutants of p53 induce global p53 protein destabilization and misfolding, followed by p53 protein aggregation. First evidence indicates that p53 can be part of protein condensates and that p53 aggregation potentially transitions through a condensate-like state. We show condensate-like states of fluorescently labeled structural mutant p53 in the nucleus of living cancer cells. We furthermore identified small molecule compounds that interact with the p53 protein and lead to dissolution of p53 structural mutant condensates. The same compounds lead to condensation of a fluorescently tagged p53 DNA-binding mutant, indicating that the identified compounds differentially alter p53 condensation behavior depending on the type of p53 mutation.In contrast to p53 aggregation inhibitors, these compounds are active on p53 condensates and do not lead to mutant p53 reactivation. Taken together our study provides evidence for structural mutant p53 condensation in living cells and tools to modulate this process.http://www.sciencedirect.com/science/article/pii/S2589004220307094Biochemistry MethodsMedical BiochemistryStructural Biology |
| spellingShingle | Clara Lemos Luise Schulze Joerg Weiske Hanna Meyer Nico Braeuer Naomi Barak Uwe Eberspächer Nicolas Werbeck Carlo Stresemann Martin Lange Ralf Lesche Nina Zablowsky Katrin Juenemann Atanas Kamburov Laura Martina Luh Thomas Markus Leissing Jeremie Mortier Michael Steckel Holger Steuber Knut Eis Ashley Eheim Patrick Steigemann Identification of Small Molecules that Modulate Mutant p53 Condensation iScience Biochemistry Methods Medical Biochemistry Structural Biology |
| title | Identification of Small Molecules that Modulate Mutant p53 Condensation |
| title_full | Identification of Small Molecules that Modulate Mutant p53 Condensation |
| title_fullStr | Identification of Small Molecules that Modulate Mutant p53 Condensation |
| title_full_unstemmed | Identification of Small Molecules that Modulate Mutant p53 Condensation |
| title_short | Identification of Small Molecules that Modulate Mutant p53 Condensation |
| title_sort | identification of small molecules that modulate mutant p53 condensation |
| topic | Biochemistry Methods Medical Biochemistry Structural Biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220307094 |
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