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Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins

Cell Death & Differentiationvolume 25pages719732 (2018) | Download Citation

Abstract

The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xL inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-xL and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-xL preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-xL could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-xL. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.

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Acknowledgements

We thank Iris Tan and Marco Herold for the lentiviral constructs, Ray Bartolo for technical assistance, and Stephanie Grabow and Gemma Kelly for the Mcl-1flox/flox mice. This work was supported by NHMRC grants (1008434, 1016701, 1113133), Cancer Council Victoria (GNT1057949) and the Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC IRIISS.

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Author notes

    • Colin Hockings

    Present address: Department of Chemical Engineering and Biotechnology, Cambridge, CB3 0AS, UK

  1. Edited by C. Borner

Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia

    • Colin Hockings
    • , Amber E. Alsop
    • , Stephanie C. Fennell
    • , Grant Dewson
    •  & Ruth M. Kluck
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia

    • Colin Hockings
    • , Amber E. Alsop
    • , Stephanie C. Fennell
    • , Grant Dewson
    •  & Ruth M. Kluck
  3. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia

    • Erinna F. Lee
    •  & W. Douglas Fairlie
  4. School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia

    • Erinna F. Lee
    •  & W. Douglas Fairlie
  5. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, Melbourne, VIC, 3086, Australia

    • Erinna F. Lee
    •  & W. Douglas Fairlie

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Conflict of interests

The authors declare that they have no competing interests.

Corresponding author

Correspondence to Ruth M. Kluck.

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DOI

https://doi.org/10.1038/s41418-017-0010-6