Mcl-1 和 Bcl-xL 在多阶段调节巨核细胞谱系的 Bak/Bax 依赖性细胞凋亡。,Cell Death and Differentiation

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Mcl-1 和 Bcl-xL 在多阶段调节巨核细胞谱系的 Bak/Bax 依赖性细胞凋亡。
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2012-Nov-01 , DOI: 10.1038/cdd.2012.88
T Kodama ₁ , H Hikita , T Kawaguchi , M Shigekawa , S Shimizu , Y Hayashi , W Li , T Miyagi , A Hosui , T Tatsumi , T Kanto , N Hiramatsu , K Kiyomizu , S Tadokoro , Y Tomiyama , N Hayashi , T Takehara

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抗凋亡 Bcl-2 家族蛋白抑制细胞凋亡的线粒体途径，参与各种造血谱系的存活，并且在造血系统恶性肿瘤中经常失调。然而，它们在巨核细胞谱系中的参与尚不清楚。在本文中，我们描述了 Mcl-1 和 Bcl-xL 在该谱系中多阶段的关键抗凋亡作用。两者的巨核细胞谱系特异性缺失与仅其中之一形成鲜明对比，导致胎肝中成熟巨核细胞的凋亡丢失和全身出血，导致胚胎致死。ABT-737 是一种 Bcl-xL/Bcl-2/Bcl-w 抑制剂，仅在成年野生型小鼠中引起血小板减少症，但在 Mcl-1 敲除小鼠中进一步诱导大量成熟巨核细胞凋亡，导致严重的出血性贫血。如果下游细胞凋亡刽子手 Bak 和 Bax 也有缺陷，所有这些表型都会完全恢复。体外研究表明，Jak 通路维持 Mcl-1 和 Bcl-xL 的表达水平，防止巨核细胞凋亡。同样，两者都参与网状血小板存活，而由于 Mcl-1 的快速蛋白酶体降解，血小板存活依赖于 Bcl-xL。总之，Mcl-1 和 Bcl-xL 调节巨核细胞谱系的存活，这对于预防发育中和成年小鼠的致命或严重出血至关重要。两者都参与网状血小板存活，而由于 Mcl-1 的快速蛋白酶体降解，血小板存活依赖于 Bcl-xL。总之，Mcl-1 和 Bcl-xL 调节巨核细胞谱系的存活，这对于预防发育中和成年小鼠的致命或严重出血至关重要。两者都参与网状血小板存活，而由于 Mcl-1 的快速蛋白酶体降解，血小板存活依赖于 Bcl-xL。总之，Mcl-1 和 Bcl-xL 调节巨核细胞谱系的存活，这对于预防发育中和成年小鼠的致命或严重出血至关重要。

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Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages.

Anti-apoptotic Bcl-2 family proteins, which inhibit the mitochondrial pathway of apoptosis, are involved in the survival of various hematopoietic lineages and are often dysregulated in hematopoietic malignancies. However, their involvement in the megakaryocytic lineage is not well understood. In the present paper, we describe the crucial anti-apoptotic role of Mcl-1 and Bcl-xL in this lineage at multistages. The megakaryocytic lineage-specific deletion of both, in sharp contrast to only one of them, caused apoptotic loss of mature megakaryocytes in the fetal liver and systemic hemorrhage, leading to embryonic lethality. ABT-737, a Bcl-xL/Bcl-2/Bcl-w inhibitor, only caused thrombocytopenia in adult wild-type mice, but further induced massive mature megakaryocyte apoptosis in the Mcl-1 knockout mice, leading to severe hemorrhagic anemia. All these phenotypes were fully restored if Bak and Bax, downstream apoptosis executioners, were also deficient. In-vitro study revealed that the Jak pathway maintained Mcl-1 and Bcl-xL expression levels, preventing megakaryoblastic cell apoptosis. Similarly, both were involved in reticulated platelet survival, whereas platelet survival was dependent on Bcl-xL due to rapid proteasomal degradation of Mcl-1. In conclusion, Mcl-1 and Bcl-xL regulate the survival of the megakaryocytic lineage, which is critically important for preventing lethal or severe hemorrhage in both developing and adult mice.

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