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

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-1Bcl-xL/Bcl-xL but not Mcl-1Bcl-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. Editor's summary: Anti-apoptotic proteins such as MCL-1 (myeloid cell leukemia-1) are potential targets for cancer therapeutics, but the full range of functions of these proteins has not been explored in vivo. MCL-1 has effects on metabolism not related to its effects on apoptosis. To evaluate and distinguish these functions, Brinkmann et al. replaced MCL-1 genes in mice with genes encoding other BCL-2 family members that are also anti-apoptotic but may not share MCL-1's other functions. MCL-1 was necessary for early embryogenesis, but this function was compensated for by the other anti-apoptotic proteins. However, later in development and after birth, the metabolic actions of MCL-1 were required and were only partially replaced by some other family members. These results may aid in the development of MCL-1 inhibitors as anticancer agents. —L. Bryan Ray [ABSTRACT FROM AUTHOR]