Targeting the cyclin-dependent kinase 5 in metastatic melanoma
© 2020 National Academy of Sciences. All rights reserved. The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Proceedings of the National Academy of Sciences
2021
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| Online Access: | https://hdl.handle.net/1721.1/135192 |
| _version_ | 1810976482885894144 |
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| author | Sharma, Samanta Zhang, Tian Michowski, Wojciech Rebecca, Vito W Xiao, Min Ferretti, Roberta Suski, Jan M Bronson, Roderick T Paulo, Joao A Frederick, Dennie Fassl, Anne Boland, Genevieve M Geng, Yan Lees, Jacqueline A Medema, Rene H Herlyn, Meenhard Gygi, Steven P Sicinski, Piotr |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Sharma, Samanta Zhang, Tian Michowski, Wojciech Rebecca, Vito W Xiao, Min Ferretti, Roberta Suski, Jan M Bronson, Roderick T Paulo, Joao A Frederick, Dennie Fassl, Anne Boland, Genevieve M Geng, Yan Lees, Jacqueline A Medema, Rene H Herlyn, Meenhard Gygi, Steven P Sicinski, Piotr |
| author_sort | Sharma, Samanta |
| collection | MIT |
| description | © 2020 National Academy of Sciences. All rights reserved. The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells. |
| first_indexed | 2024-09-23T08:55:59Z |
| format | Article |
| id | mit-1721.1/135192 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:55:59Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1351922023-12-08T20:38:20Z Targeting the cyclin-dependent kinase 5 in metastatic melanoma Sharma, Samanta Zhang, Tian Michowski, Wojciech Rebecca, Vito W Xiao, Min Ferretti, Roberta Suski, Jan M Bronson, Roderick T Paulo, Joao A Frederick, Dennie Fassl, Anne Boland, Genevieve M Geng, Yan Lees, Jacqueline A Medema, Rene H Herlyn, Meenhard Gygi, Steven P Sicinski, Piotr Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Biology © 2020 National Academy of Sciences. All rights reserved. The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells. 2021-10-27T20:22:24Z 2021-10-27T20:22:24Z 2020 2021-07-20T18:31:44Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135192 en 10.1073/PNAS.1912617117 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Sharma, Samanta Zhang, Tian Michowski, Wojciech Rebecca, Vito W Xiao, Min Ferretti, Roberta Suski, Jan M Bronson, Roderick T Paulo, Joao A Frederick, Dennie Fassl, Anne Boland, Genevieve M Geng, Yan Lees, Jacqueline A Medema, Rene H Herlyn, Meenhard Gygi, Steven P Sicinski, Piotr Targeting the cyclin-dependent kinase 5 in metastatic melanoma |
| title | Targeting the cyclin-dependent kinase 5 in metastatic melanoma |
| title_full | Targeting the cyclin-dependent kinase 5 in metastatic melanoma |
| title_fullStr | Targeting the cyclin-dependent kinase 5 in metastatic melanoma |
| title_full_unstemmed | Targeting the cyclin-dependent kinase 5 in metastatic melanoma |
| title_short | Targeting the cyclin-dependent kinase 5 in metastatic melanoma |
| title_sort | targeting the cyclin dependent kinase 5 in metastatic melanoma |
| url | https://hdl.handle.net/1721.1/135192 |
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