Cdk6’s functions are critically regulated by its unique C-terminus
Summary: The vital cell cycle machinery is tightly regulated and alterations of its central signaling hubs are a hallmark of cancer. The activity of CDK6 is controlled by interaction with several partners including cyclins and INK4 proteins, which have been shown to mainly bind to the amino-terminal...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224029249 |
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| author | Alessia Schirripa Helge Schöppe Sofie Nebenfuehr Markus Zojer Thorsten Klampfl Valentina Kugler Belinda S. Maw Huriye Ceylan Iris Z. Uras Lisa Scheiblecker Elisabeth Gamper Ulrich Stelzl Eduard Stefan Teresa Kaserer Veronika Sexl Karoline Kollmann |
| author_facet | Alessia Schirripa Helge Schöppe Sofie Nebenfuehr Markus Zojer Thorsten Klampfl Valentina Kugler Belinda S. Maw Huriye Ceylan Iris Z. Uras Lisa Scheiblecker Elisabeth Gamper Ulrich Stelzl Eduard Stefan Teresa Kaserer Veronika Sexl Karoline Kollmann |
| author_sort | Alessia Schirripa |
| collection | DOAJ |
| description | Summary: The vital cell cycle machinery is tightly regulated and alterations of its central signaling hubs are a hallmark of cancer. The activity of CDK6 is controlled by interaction with several partners including cyclins and INK4 proteins, which have been shown to mainly bind to the amino-terminal lobe. We analyzed the impact of CDK6’s C-terminus on its functions in a leukemia model, revealing a central role in promoting proliferation. C-terminally truncated Cdk6 (Cdk6 ΔC) shows reduced nuclear translocation and therefore chromatin interaction and fails to enhance proliferation and disease progression. The combination of proteomic analysis and protein modeling highlights that Cdk6’s C-terminus is essential for protein flexibility and for its binding potential to cyclin D, p27Kip1 and INK4 proteins but not cyclin B. We demonstrate that the C-terminus is a unique and essential part of the CDK6 protein, regulating interaction partner binding and therefore CDK6’s functionality. |
| format | Article |
| id | doaj-art-50f9aaca33e34a8e823674aad486339c |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-50f9aaca33e34a8e823674aad486339c2025-01-20T04:17:48ZengElsevieriScience2589-00422025-02-01282111697Cdk6’s functions are critically regulated by its unique C-terminusAlessia Schirripa0Helge Schöppe1Sofie Nebenfuehr2Markus Zojer3Thorsten Klampfl4Valentina Kugler5Belinda S. Maw6Huriye Ceylan7Iris Z. Uras8Lisa Scheiblecker9Elisabeth Gamper10Ulrich Stelzl11Eduard Stefan12Teresa Kaserer13Veronika Sexl14Karoline Kollmann15Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaTyrolean Cancer Research Institute (TKFI), Innrain 66, 6020 Innsbruck, Austria; Institute of Molecular Biology and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria; Field of Excellence BioHealth - University of Graz, Graz, AustriaTyrolean Cancer Research Institute (TKFI), Innrain 66, 6020 Innsbruck, Austria; Institute of Molecular Biology and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, AustriaInstitute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; University of Innsbruck, Innsbruck, AustriaInstitute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Corresponding authorSummary: The vital cell cycle machinery is tightly regulated and alterations of its central signaling hubs are a hallmark of cancer. The activity of CDK6 is controlled by interaction with several partners including cyclins and INK4 proteins, which have been shown to mainly bind to the amino-terminal lobe. We analyzed the impact of CDK6’s C-terminus on its functions in a leukemia model, revealing a central role in promoting proliferation. C-terminally truncated Cdk6 (Cdk6 ΔC) shows reduced nuclear translocation and therefore chromatin interaction and fails to enhance proliferation and disease progression. The combination of proteomic analysis and protein modeling highlights that Cdk6’s C-terminus is essential for protein flexibility and for its binding potential to cyclin D, p27Kip1 and INK4 proteins but not cyclin B. We demonstrate that the C-terminus is a unique and essential part of the CDK6 protein, regulating interaction partner binding and therefore CDK6’s functionality.http://www.sciencedirect.com/science/article/pii/S2589004224029249BiochemistryMolecular StructureStructural biologyCancer |
| spellingShingle | Alessia Schirripa Helge Schöppe Sofie Nebenfuehr Markus Zojer Thorsten Klampfl Valentina Kugler Belinda S. Maw Huriye Ceylan Iris Z. Uras Lisa Scheiblecker Elisabeth Gamper Ulrich Stelzl Eduard Stefan Teresa Kaserer Veronika Sexl Karoline Kollmann Cdk6’s functions are critically regulated by its unique C-terminus iScience Biochemistry Molecular Structure Structural biology Cancer |
| title | Cdk6’s functions are critically regulated by its unique C-terminus |
| title_full | Cdk6’s functions are critically regulated by its unique C-terminus |
| title_fullStr | Cdk6’s functions are critically regulated by its unique C-terminus |
| title_full_unstemmed | Cdk6’s functions are critically regulated by its unique C-terminus |
| title_short | Cdk6’s functions are critically regulated by its unique C-terminus |
| title_sort | cdk6 s functions are critically regulated by its unique c terminus |
| topic | Biochemistry Molecular Structure Structural biology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224029249 |
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