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

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-07-03 DOI:10.1126/science.adw1836

Kerstin Brinkmann, Kate McArthur, Shezlie Malelang, Leonie Gibson, Annli Tee, Sheik Nadeem Elahee Doomun, Caitlin L. Rowe, Philip Arandjelovic, Julia M. Marchingo, Damian D’Silva, Annabell Bachem, Simon Monard, Lauren G. Whelan, Grant Dewson, Tracy L. Putoczki, Philippe Bouillet, Nai Yang Fu, Kristin K. Brown, Andrew J. Kueh, Verena C. Wimmer, Marco J. Herold, Tim Thomas, Anne K. Voss, Andreas Strasser

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引用次数: 0

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.

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体内MCL-1抗凋亡与凋亡无关功能的相对重要性

抗凋亡蛋白MCL-1（髓样细胞白血病-1）对胚胎发生和许多细胞类型的存活至关重要，这些细胞类型可以耐受其亲属BCL-XL和BCL-2的缺失。MCL-1在代谢中与凋亡无关的作用可能有助于这一需求，尽管它们与胚胎发生和出生后生活的相关性尚不清楚。我们推测BCL-XL和BCL-2可能替代MCL-1的抗凋亡功能，但不能替代其与凋亡无关的功能。用BCL-XL或BCL-2替代MCL-1可通过挽救MCL-1−/−着床前致死性来支持胚胎发育。Mcl-1 Bcl-xL/Bcl-xL而不是Mcl-1 Bcl-2/Bcl-2小鼠出生在混合背景下，尽管它们表现出代谢缺陷。因此，MCL-1与凋亡无关的功能在后期发育中显得至关重要，BCL-XL而不是BCL-2部分补偿。这些发现阐明了MCL-1的独特生理作用，为MCL-1抑制剂作为癌症治疗药物的发展提供了重要信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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