Relative importance of the anti-apoptotic versus apoptosis-unrelated functions of MCL-1 in vivo
- Author(s)
- Brinkmann, K; McArthur, K; Malelang, S; Gibson, L; Tee, A; Elahee Doomun, SN; Rowe, CL; Arandjelovic, P; Marchingo, JM; D'Silva, D; Bachem, A; Monard, S; Whelan, LG; Dewson, G; Putoczki, TL; Bouillet, P; Fu, NY; Brown, KK; Kueh, AJ; Wimmer, VC; Herold, MJ; Thomas, T; Voss, AK; Strasser, A;
- Journal Title
- Science
- Publication Type
- Online publication before print
- Abstract
- The anti-apoptotic protein MCL-1 (myeloid cell leukemia-1) is essential for embryogenesis and the survival of many cell types that tolerate loss of its relatives, BCL-XL and BCL-2. Apoptosis-unrelated roles of MCL-1 in metabolism may contribute to this requirement, though their relevance for embryogenesis and postnatal life remains unclear. We hypothesized that BCL-XL and BCL-2 may substitute MCL-1's anti-apoptotic but not its apoptosis-unrelated functions. Replacing MCL-1 with BCL-XL or BCL-2 supported embryo development by rescuing the Mcl-1(-/-) preimplantation lethality. Mcl-1(Bcl-xL/Bcl-xL) but not Mcl-1(Bcl-2/Bcl-2) mice were born on a mixed background, though they showed metabolic defects. Thus MCL-1's apoptosis-unrelated functions appear critical in later development, with BCL-XL, but not BCL-2, partially compensating. These findings clarify MCL-1's distinct physiological roles, critically informing MCL-1 inhibitor development as cancer therapeutics.
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1126/science.adw1836
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- Refer to copyright notice on published article.
Creation Date: 2025-07-22 03:31:00
Last Modified: 2025-07-22 03:31:16