Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7
| Autor: | Wayne J. Fairbrother, Pawan Bir Kohli, Adam R. Johnson, Lisa D. Belmont, Ingrid E. Wertz, Mike Eby, Toru Okamoto, Mark L. Chiu, Cynthia Lam, Somasekar Seshagiri, Jinfeng Liu, Elizabeth Helgason, Jennie R. Lill, Kanan Pujara, Saritha Kusam, Heather Maecker, Vishva M. Dixit, Karen O'Rourke, Mary J. C. Ludlam, Peter K. Jackson, Wendy Sandoval, Erin C. Dueber, Daniel Anderson, Kevin G. Leong, James A. Ernst, David C.S. Huang, Joshua S. Kaminker |
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| Rok vydání: | 2011 |
| Předmět: |
Proteasome Endopeptidase Complex
Programmed cell death F-Box-WD Repeat-Containing Protein 7 Paclitaxel Ubiquitin-Protein Ligases Mitosis Apoptosis Cell Cycle Proteins Biology medicine.disease_cause Cell Line Polyploidy Mice Tubulin Cell Line Tumor medicine Animals Humans MCL1 RNA Messenger Phosphorylation Multidisciplinary F-Box Proteins Fibroblasts Cell cycle Tubulin Modulators Ubiquitin ligase Cell Transformation Neoplastic Proto-Oncogene Proteins c-bcl-2 Drug Resistance Neoplasm Pharmacogenetics Vincristine Mitotic exit Ubiquitin ligase complex Immunology biology.protein Cancer research Myeloid Cell Leukemia Sequence 1 Protein Carcinogenesis Protein Binding |
| Zdroj: | Nature. 471:110-114 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature09779 |
| Popis: | Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics. |
| Databáze: | OpenAIRE |
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