E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol
<p dir="ltr">Chemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (<i>FBW7<...
محفوظ في:
| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , |
| منشور في: |
2023
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| _version_ | 1864513509268652032 |
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| author | Kripa S. Keyan (17807771) |
| author2 | Rania Alanany (19256338) Amira Kohil (15257285) Omar M. Khan (17807774) |
| author2_role | author author author |
| author_facet | Kripa S. Keyan (17807771) Rania Alanany (19256338) Amira Kohil (15257285) Omar M. Khan (17807774) |
| author_role | author |
| dc.creator.none.fl_str_mv | Kripa S. Keyan (17807771) Rania Alanany (19256338) Amira Kohil (15257285) Omar M. Khan (17807774) |
| dc.date.none.fl_str_mv | 2023-01-13T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3390/cancers15020505 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/E3_Ubiquitin_Ligase_i_TRIP12_i_Controls_Exit_from_Mitosis_via_Positive_Regulation_of_i_MCL-1_i_in_Response_to_Taxol/26508451 |
| 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 Clinical sciences Oncology and carcinogenesis Reproductive medicine FBW7 MCL-1 chemotherapy Taxol proteasomal degradation mitotic arrest |
| dc.title.none.fl_str_mv | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Chemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (<i>FBW7</i>) mutations leads to the accumulation of its substrate<i> MCL-1 </i>which is associated with Taxol resistance in human cancers. We recently showed that E3 ubiquitin ligase <i>TRIP12</i> is a negative regulator of <i>FBW7</i> protein. In this study, we find that Taxol-induced mitotic block in cancer cells is partly controlled by TRIP12 via its positive regulation of <i>MCL-1</i> protein. Genetic inhibition of TRIP12 accelerates <i>MCL-1 </i>protein degradation in mitosis. Notably, introducing double-point mutations in lysines 404/412 of <i>FBW7</i> to arginine which makes it resistant to proteasomal degradation, leads to the sharp reduction of MCL-1 protein levels and sensitizes cancer cells to Taxol-induced cell death. Finally, <i>TRIP12</i> deletion leads to enhanced mitotic arrest and cell death in an<i> FBW7</i> and <i>MCL-1</i> dependent manner in multiple cell lines including colorectal and ovarian cancer but not in breast cancer. Thus, the <i>TRIP12/FBW7/MCL-1</i> axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer.</p><h2>Other Information</h2><p dir="ltr">Published in: Cancers<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/10.3390/cancers15020505" target="_blank">https://dx.doi.org/10.3390/cancers15020505</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_2ac7eee4eede8196dbedd9d1387a6d37 |
| identifier_str_mv | 10.3390/cancers15020505 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26508451 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to TaxolKripa S. Keyan (17807771)Rania Alanany (19256338)Amira Kohil (15257285)Omar M. Khan (17807774)Biomedical and clinical sciencesClinical sciencesOncology and carcinogenesisReproductive medicineFBW7MCL-1chemotherapyTaxolproteasomal degradationmitotic arrest<p dir="ltr">Chemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (<i>FBW7</i>) mutations leads to the accumulation of its substrate<i> MCL-1 </i>which is associated with Taxol resistance in human cancers. We recently showed that E3 ubiquitin ligase <i>TRIP12</i> is a negative regulator of <i>FBW7</i> protein. In this study, we find that Taxol-induced mitotic block in cancer cells is partly controlled by TRIP12 via its positive regulation of <i>MCL-1</i> protein. Genetic inhibition of TRIP12 accelerates <i>MCL-1 </i>protein degradation in mitosis. Notably, introducing double-point mutations in lysines 404/412 of <i>FBW7</i> to arginine which makes it resistant to proteasomal degradation, leads to the sharp reduction of MCL-1 protein levels and sensitizes cancer cells to Taxol-induced cell death. Finally, <i>TRIP12</i> deletion leads to enhanced mitotic arrest and cell death in an<i> FBW7</i> and <i>MCL-1</i> dependent manner in multiple cell lines including colorectal and ovarian cancer but not in breast cancer. Thus, the <i>TRIP12/FBW7/MCL-1</i> axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer.</p><h2>Other Information</h2><p dir="ltr">Published in: Cancers<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/10.3390/cancers15020505" target="_blank">https://dx.doi.org/10.3390/cancers15020505</a></p>2023-01-13T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3390/cancers15020505https://figshare.com/articles/journal_contribution/E3_Ubiquitin_Ligase_i_TRIP12_i_Controls_Exit_from_Mitosis_via_Positive_Regulation_of_i_MCL-1_i_in_Response_to_Taxol/26508451CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/265084512023-01-13T09:00:00Z |
| spellingShingle | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol Kripa S. Keyan (17807771) Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Reproductive medicine FBW7 MCL-1 chemotherapy Taxol proteasomal degradation mitotic arrest |
| status_str | publishedVersion |
| title | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_full | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_fullStr | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_full_unstemmed | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_short | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_sort | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| topic | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Reproductive medicine FBW7 MCL-1 chemotherapy Taxol proteasomal degradation mitotic arrest |