Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7
Top Cited Papers
- 2 March 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 471 (7336), 110-114
- https://doi.org/10.1038/nature09779
Abstract
Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics(1). 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(1). These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms(2). The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear(2). 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.Keywords
This publication has 20 references indexed in Scilit:
- Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and ApoptosisMolecular and Cellular Biology, 2010
- Evidence that Mitotic Exit Is a Better Cancer Therapeutic Target Than Spindle AssemblyCancer Cell, 2009
- Recognition and Processing of Ubiquitin-Protein Conjugates by the ProteasomeAnnual Review of Biochemistry, 2009
- Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancerNature Reviews Cancer, 2008
- Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidyOncogene, 2008
- FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiationNature Reviews Cancer, 2008
- The reversibility of mitotic exit in vertebrate cellsNature, 2006
- Mule/ARF-BP1, a BH3-Only E3 Ubiquitin Ligase, Catalyzes the Polyubiquitination of Mcl-1 and Regulates ApoptosisCell, 2005
- Differential Targeting of Prosurvival Bcl-2 Proteins by Their BH3-Only Ligands Allows Complementary Apoptotic FunctionMolecular Cell, 2005
- A 20s complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin BCell, 1995