A Truncated Form of IKKα Is Responsible for Specific Nuclear IKK Activity in Colorectal Cancer
Nuclear IKKα regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKKα activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples a...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2012-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124712002689 |
| _version_ | 1818114198537764864 |
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| author | Pol Margalef Vanessa Fernández-Majada Alberto Villanueva Ricard Garcia-Carbonell Mar Iglesias Laura López María Martínez-Iniesta Jordi Villà-Freixa Mari Carmen Mulero Montserrat Andreu Ferran Torres Marty W. Mayo Anna Bigas Lluis Espinosa |
| author_facet | Pol Margalef Vanessa Fernández-Majada Alberto Villanueva Ricard Garcia-Carbonell Mar Iglesias Laura López María Martínez-Iniesta Jordi Villà-Freixa Mari Carmen Mulero Montserrat Andreu Ferran Torres Marty W. Mayo Anna Bigas Lluis Espinosa |
| author_sort | Pol Margalef |
| collection | DOAJ |
| description | Nuclear IKKα regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKKα activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples and found a significant association between the presence of nuclear IKK and malignancy. Importantly, the nucleus of tumor cells contains an active IKKα isoform with a predicted molecular weight of 45 kDa (p45-IKKα) that includes the kinase domain but lacks several regulatory regions. Active nuclear p45-IKKα forms a complex with nonactive IKKα and NEMO that mediates phosphorylation of SMRT and histone H3. Proteolytic cleavage of FL-IKKα into p45-IKKα is required for preventing the apoptosis of CRC cells in vitro and sustaining tumor growth in vivo. Our findings identify a potentially druggable target for treating patients with advance refractory CRC. |
| first_indexed | 2024-12-11T03:46:55Z |
| format | Article |
| id | doaj.art-e573cc73b601452a8359406a930971e0 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T03:46:55Z |
| publishDate | 2012-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-e573cc73b601452a8359406a930971e02022-12-22T01:22:01ZengElsevierCell Reports2211-12472012-10-012484085410.1016/j.celrep.2012.08.028A Truncated Form of IKKα Is Responsible for Specific Nuclear IKK Activity in Colorectal CancerPol Margalef0Vanessa Fernández-Majada1Alberto Villanueva2Ricard Garcia-Carbonell3Mar Iglesias4Laura López5María Martínez-Iniesta6Jordi Villà-Freixa7Mari Carmen Mulero8Montserrat Andreu9Ferran Torres10Marty W. Mayo11Anna Bigas12Lluis Espinosa13Institut Municipal d’Investigacions Mèdiques (IMIM), Institut Hospital del Mar d'Investigacions Mèdiques, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, SpainInstitut Municipal d’Investigacions Mèdiques (IMIM), Institut Hospital del Mar d'Investigacions Mèdiques, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, SpainLaboratori de Recerca Translacional, IDIBELL-Institut Català d’Oncologia Gran Via km 2.7, Hospitalet, Barcelona 08907, SpainInstitut Municipal d’Investigacions Mèdiques (IMIM), Institut Hospital del Mar d'Investigacions Mèdiques, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, SpainDepartment of Pathology, Institut Hospital del Mar d'Investigacions Mèdiques, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, SpainDepartment of Pathology, Institut Hospital del Mar d'Investigacions Mèdiques, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, SpainLaboratori de Recerca Translacional, IDIBELL-Institut Català d’Oncologia Gran Via km 2.7, Hospitalet, Barcelona 08907, SpainComputational Biochemistry and Biophysics Laboratory, IMIM-Hospital del Mar, Universitat Pompeu Fabra, Barcelona 08003, SpainInstitut Municipal d’Investigacions Mèdiques (IMIM), Institut Hospital del Mar d'Investigacions Mèdiques, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, SpainDepartment of Gastroenterology, IMIM-Hospital del Mar, Universitat Pompeu Fabra, Barcelona 08003, SpainDepartment of Statistics, UAB, Barcelona 08193, SpainDepartment of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA 22908, USAInstitut Municipal d’Investigacions Mèdiques (IMIM), Institut Hospital del Mar d'Investigacions Mèdiques, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, SpainInstitut Municipal d’Investigacions Mèdiques (IMIM), Institut Hospital del Mar d'Investigacions Mèdiques, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, SpainNuclear IKKα regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKKα activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples and found a significant association between the presence of nuclear IKK and malignancy. Importantly, the nucleus of tumor cells contains an active IKKα isoform with a predicted molecular weight of 45 kDa (p45-IKKα) that includes the kinase domain but lacks several regulatory regions. Active nuclear p45-IKKα forms a complex with nonactive IKKα and NEMO that mediates phosphorylation of SMRT and histone H3. Proteolytic cleavage of FL-IKKα into p45-IKKα is required for preventing the apoptosis of CRC cells in vitro and sustaining tumor growth in vivo. Our findings identify a potentially druggable target for treating patients with advance refractory CRC.http://www.sciencedirect.com/science/article/pii/S2211124712002689 |
| spellingShingle | Pol Margalef Vanessa Fernández-Majada Alberto Villanueva Ricard Garcia-Carbonell Mar Iglesias Laura López María Martínez-Iniesta Jordi Villà-Freixa Mari Carmen Mulero Montserrat Andreu Ferran Torres Marty W. Mayo Anna Bigas Lluis Espinosa A Truncated Form of IKKα Is Responsible for Specific Nuclear IKK Activity in Colorectal Cancer Cell Reports |
| title | A Truncated Form of IKKα Is Responsible for Specific Nuclear IKK Activity in Colorectal Cancer |
| title_full | A Truncated Form of IKKα Is Responsible for Specific Nuclear IKK Activity in Colorectal Cancer |
| title_fullStr | A Truncated Form of IKKα Is Responsible for Specific Nuclear IKK Activity in Colorectal Cancer |
| title_full_unstemmed | A Truncated Form of IKKα Is Responsible for Specific Nuclear IKK Activity in Colorectal Cancer |
| title_short | A Truncated Form of IKKα Is Responsible for Specific Nuclear IKK Activity in Colorectal Cancer |
| title_sort | truncated form of ikkα is responsible for specific nuclear ikk activity in colorectal cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124712002689 |
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