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SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction

Abstract

The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer1 and T-cell acute lymphoblastic leukaemia (T-ALL)2. In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL3,4,5, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun6, Myc7, cyclin E8 and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth10, overexpression of Jun, Myc or notch 1 can also induce programmed cell death11. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCFFBW7 (a SKP1–cullin-1–F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL.

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Figure 1: MCL1 stability is controlled by FBW7.
Figure 2: Phosphorylation of MCL1 by GSK3 triggers the interaction of MCL1 with FBW7.
Figure 3: FBW7 promotes MCL1 ubiquitylation and destruction in a GSK3-mediated phosphorylation-dependent manner.
Figure 4: Elevated MCL1 expression protects FBW7-deficient T-ALL cell lines from ABT-737-induced apoptosis.

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Acknowledgements

We thank J. Lawler, C. Schorl, Q. Zhang and S. Glueck for critical reading of the manuscript, J. DeCaprio, M.-C. Hung, M. A. Kelliher, W. Harper and W. Hahn for providing reagents, L. Cantley and A. Toker for suggestions, I. Wertz and V. Dixit for sharing unpublished data, and members of the Wei and DePinho labs for useful discussions. W.W. is a Kimmel Scholar and V Scholar. This work was supported in part by the Emerald Foundation New Investigator award (W.W.), the Leukemia and Lymphoma Society Special Fellow award (W.W.) and a grant from the National Institutes of Health (W.W.; GM089763). R.A.D. is an American Cancer Society Research Professor and is supported by the Robert A. and Renée E. Belfer Foundation Institute for Applied Cancer Science.

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H.I. performed most of the experiments with critical assistance from S.S. and D.G. A.T., L.W. and A.W.L. also helped perform a portion of the experiments. I.O. performed the Fbw7 conditional knockout mouse experiments, and A.L.C. performed the orthotopic engraftment mouse experiments. B.Z. performed the mass spectrometry analysis, and Y.X. and R.S.M. helped to perform the experiments with tumours derived from the TKO mice. A.G. helped to perform the experiments with the human T-ALL clinical samples. W.W., R.A.D. and K.I.N. designed the experiments with assistance from J.A., J. S., A.L.K., H.I., S.P.G. and T.L. W.W. supervised the study. W.W. wrote the manuscript with help from H.I. and S.S. All authors commented on the manuscript.

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Correspondence to Wenyi Wei.

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The authors declare no competing financial interests.

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Inuzuka, H., Shaik, S., Onoyama, I. et al. SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471, 104–109 (2011). https://doi.org/10.1038/nature09732

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