FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2
<p dir="ltr">FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-M...
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| مؤلفون آخرون: | , , , , , , , , |
| منشور في: |
2023
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| _version_ | 1864513507118022656 |
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| author | Rafael Jiménez-Izquierdo (19482373) |
| author2 | Rosario Morrugares (19482376) Lucía Suanes-Cobos (19482379) Alejandro Correa-Sáez (13027239) Martín Garrido-Rodríguez (19482382) Laura Cerero-Tejero (19482385) Omar M. Khan (17807774) Susana de la Luna (266616) Rocío Sancho (14908566) Marco A. Calzado (7833170) |
| author2_role | author author author author author author author author author |
| author_facet | Rafael Jiménez-Izquierdo (19482373) Rosario Morrugares (19482376) Lucía Suanes-Cobos (19482379) Alejandro Correa-Sáez (13027239) Martín Garrido-Rodríguez (19482382) Laura Cerero-Tejero (19482385) Omar M. Khan (17807774) Susana de la Luna (266616) Rocío Sancho (14908566) Marco A. Calzado (7833170) |
| author_role | author |
| dc.creator.none.fl_str_mv | Rafael Jiménez-Izquierdo (19482373) Rosario Morrugares (19482376) Lucía Suanes-Cobos (19482379) Alejandro Correa-Sáez (13027239) Martín Garrido-Rodríguez (19482382) Laura Cerero-Tejero (19482385) Omar M. Khan (17807774) Susana de la Luna (266616) Rocío Sancho (14908566) Marco A. Calzado (7833170) |
| dc.date.none.fl_str_mv | 2023-03-18T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41419-023-05724-0 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/FBXW7_tumor_suppressor_regulation_by_dualspecificity_tyrosine-regulated_kinase_2/26830177 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences FBXW7 F-box Proteins SCF E3 Ubiquitin Ligase Tumor Suppressor DYRK2 Phosphorylation Chemotherapy |
| dc.title.none.fl_str_mv | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-Myc, Cyclin E1, mTOR, and Notch1-IC. FBXW7 inactivation in human cancers results from a somatic mutation or downregulation of its protein levels. This work describes a novel regulatory mechanism for FBXW7 dependent on the serine/threonine protein kinase DYRK2. We show that DYRK2 interacts with and phosphorylates FBXW7 resulting in its proteasome-mediated degradation. DYRK2-dependent FBXW7 destabilization is independent of its ubiquitin ligase activity. The functional analysis demonstrates the existence of DYRK2-dependent regulatory mechanisms for key FBXW7 substrates. Finally, we provide evidence indicating that DYRK2-dependent regulation of FBXW7 protein accumulation contributes to cytotoxic effects in response to chemotherapy agents such as Doxorubicin or Paclitaxel in colorectal cancer cell lines and to BET inhibitors in T-cell acute lymphoblastic leukemia cell lines. Altogether, this work reveals a new regulatory axis, DYRK2/FBXW7, which provides an understanding of the role of these two proteins in tumor progression and DNA damage responses.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Death & Disease<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41419-023-05724-0" target="_blank">https://dx.doi.org/10.1038/s41419-023-05724-0</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_0dc783552ed042aa22578c88ad18de81 |
| identifier_str_mv | 10.1038/s41419-023-05724-0 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26830177 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2Rafael Jiménez-Izquierdo (19482373)Rosario Morrugares (19482376)Lucía Suanes-Cobos (19482379)Alejandro Correa-Sáez (13027239)Martín Garrido-Rodríguez (19482382)Laura Cerero-Tejero (19482385)Omar M. Khan (17807774)Susana de la Luna (266616)Rocío Sancho (14908566)Marco A. Calzado (7833170)Biomedical and clinical sciencesOncology and carcinogenesisPharmacology and pharmaceutical sciencesFBXW7F-box ProteinsSCF E3 Ubiquitin LigaseTumor SuppressorDYRK2PhosphorylationChemotherapy<p dir="ltr">FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-Myc, Cyclin E1, mTOR, and Notch1-IC. FBXW7 inactivation in human cancers results from a somatic mutation or downregulation of its protein levels. This work describes a novel regulatory mechanism for FBXW7 dependent on the serine/threonine protein kinase DYRK2. We show that DYRK2 interacts with and phosphorylates FBXW7 resulting in its proteasome-mediated degradation. DYRK2-dependent FBXW7 destabilization is independent of its ubiquitin ligase activity. The functional analysis demonstrates the existence of DYRK2-dependent regulatory mechanisms for key FBXW7 substrates. Finally, we provide evidence indicating that DYRK2-dependent regulation of FBXW7 protein accumulation contributes to cytotoxic effects in response to chemotherapy agents such as Doxorubicin or Paclitaxel in colorectal cancer cell lines and to BET inhibitors in T-cell acute lymphoblastic leukemia cell lines. Altogether, this work reveals a new regulatory axis, DYRK2/FBXW7, which provides an understanding of the role of these two proteins in tumor progression and DNA damage responses.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Death & Disease<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41419-023-05724-0" target="_blank">https://dx.doi.org/10.1038/s41419-023-05724-0</a></p>2023-03-18T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41419-023-05724-0https://figshare.com/articles/journal_contribution/FBXW7_tumor_suppressor_regulation_by_dualspecificity_tyrosine-regulated_kinase_2/26830177CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/268301772023-03-18T09:00:00Z |
| spellingShingle | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 Rafael Jiménez-Izquierdo (19482373) Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences FBXW7 F-box Proteins SCF E3 Ubiquitin Ligase Tumor Suppressor DYRK2 Phosphorylation Chemotherapy |
| status_str | publishedVersion |
| title | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_full | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_fullStr | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_full_unstemmed | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_short | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_sort | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| topic | Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences FBXW7 F-box Proteins SCF E3 Ubiquitin Ligase Tumor Suppressor DYRK2 Phosphorylation Chemotherapy |