Relative importance of the anti-apoptotic versus apoptosis-unrelated functions of MCL-1 in vivo

Brinkmann, K; McArthur, K; Malelang, S; Gibson, L; Tee, A; Elahee Doomun, SN; Rowe, CL; Arandjelovic, P; Marchingo, JM; D&#39;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

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;
Details: Publication Year 2025-09-04,Volume 389,Issue #6764,Page 1003-1011
Journal Title: Science
Publication Type: Research article
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, although 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, although 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.
Publisher: American Association for the Advancement of Science
Keywords: *Myeloid Cell Leukemia Sequence 1 Protein/genetics/physiology/metabolism; Animals; *Apoptosis/genetics; *bcl-X Protein/genetics/metabolism/physiology; Mice; *Proto-Oncogene Proteins c-bcl-2/genetics/metabolism/physiology; *Embryonic Development/genetics; Female; Mice, Knockout
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1126/science.adw1836
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-07-22 03:31:00

Last Modified: 2025-09-30 04:36:29