Relative importance of the anti-apoptotic versus apoptosis-unrelated functions of MCL-1 in vivo
Kerstin Brinkmann, Kate McArthur, Shezlie Malelang, Leonie Gibson, Annli Tee, Sheik Nadeem Elahee Doomun, Caitlin L. Rowe, Philip Arandjelovic, Julia M. Marchingo, Damian B. D’Silva, Annabell Bachem, Simon Monard, Lauren Whelan, Grant Dewson, Tracy L. Putoczki, Philippe Bouillet, Nai Yang Fu, Kristin Brown, Andrew J. Kueh, Verena C. Wimmer, Marco J. Herold, Tim Thomas, Anne K. Voss, Andreas Strasser
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.