Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7
- Wertz, IE; Kusam, S; Lam, C; Okamoto, T; Sandoval, W; Anderson, DJ; Helgason, E; Ernst, JA; Eby, M; Liu, JF; Belmont, LD; Kaminker, JS; O'Rourke, KM; Pujara, K; Kohli, PB; Johnson, AR; Chiu, ML; Lill, JR; Jackson, PK; Fairbrother, WJ; Seshagiri, S; Ludlam, MJC; Leong, KG; Dueber, EC; Maecker, H; Huang, DCS; Dixit, VM;
Publication Year 2011-03-03, Volume 471, Issue #7336, Page 110-114
- Journal Title
- Publication Type
- Journal Article
- 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.
- NATURE PUBLISHING GROUP
- UBIQUITIN LIGASE; MITOTIC EXIT; CANCER; CELLS; APOPTOSIS; RESISTANCE; CATALYZES; PROTEINS; DIVISION
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2011-03-03 12:00:00Last Modified: 0001-01-01 12:00:00