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

Colin Hockings1,2,3, Amber E Alsop1,2, Stephanie C Fennell1,2

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

Cell Death and Differentiation
|February 21, 2018
PubMed

Insights

Bcl-2 proteins Mcl-1 and Bcl-xL block apoptosis by sequestering proteins. Understanding these interactions, particularly Bak sequestration, is key to overcoming resistance to cancer therapies like BH3 mimetics.

Area of Science:

  • Molecular Biology
  • Cell Death Pathways
  • Cancer Therapeutics

Background:

  • Prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xL are critical regulators of apoptosis.
  • These proteins inhibit programmed cell death by sequestering BH3-only proteins (MODE 1) or effector proteins Bak and Bax (MODE 2).
  • Understanding these sequestration mechanisms is crucial for developing strategies to overcome therapeutic resistance.

Purpose of the Study:

  • To elucidate the distinct contributions of MODE 1 and MODE 2 in blocking apoptosis.
  • To investigate how specific Bcl-2 family protein interactions influence resistance to cell death.
  • To explore mechanisms for bypassing resistance to anti-cancer treatments.

Main Methods:

  • Examination of prescribed mixtures of Bcl-2 family proteins.
  • Analysis of protein sequestration dynamics in the presence of Bim, Bid, and Bak.
  • Investigation of Bcl-xL's interaction with Bak in response to the BH3 mimetic ABT-737.

Main Results:

  • In a Bim and Bak mixture, both Bcl-xL and Mcl-1 sequestered Bim and activated Bak.
  • In a Bid and Bak mixture, Bcl-xL preferentially sequestered Bid, while Mcl-1 preferentially sequestered Bak.
  • Bcl-xL demonstrated the ability to sequester Bak even in the presence of the BH3 mimetic ABT-737.

Conclusions:

  • The specific interactions between Bcl-2 proteins and their targets (Bid, Bim, Bak, Bax) vary depending on the protein composition.
  • Bak sequestration plays a significant role in cellular resistance to apoptosis.
  • These findings underscore the importance of Bak sequestration in resistance to anti-cancer therapies, including BH3 mimetics.

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