Programmed anuclear cell death delimits platelet life span
Programmed anuclear cell death delimits platelet life span
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DOI：
10.1016/j.cell.2007.01.037
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发表时间：
2007-03-23
期刊：
影响因子：
64.5
通讯作者：
Kile, Benjamin T.
中科院分区：
文献类型：
--
作者：
Mason, Kylie D.;Carpinelli, Marina R.;Kile, Benjamin T.
血小板是对血液凝固和伤口愈合至关重要的无核细胞质碎片。尽管有很多猜测，但决定它们在循环中的寿命的因素尚不清楚。我们在这里展示了细胞凋亡的内在程序，控制血小板存活并决定它们的寿命。促生存Bcl-X-L抑制Bak的促凋亡活性以维持血小板存活，但随着Bcl-X-L的降解，衰老的血小板会导致细胞死亡。基因消融或Bcl-X-L的药理学失活可减少血小板半衰期，并以剂量依赖的方式引起血小板减少症。Bak的缺失纠正了这些缺陷，并且来自Bak缺陷小鼠的血小板比正常小鼠活得更长。因此，在默认情况下，血小板在基因上被设定为死于细胞凋亡。Bcl-X-L和Bak之间的拮抗平衡构成了一个决定血小板寿命的分子钟：这代表了细胞稳态的重要范式，对影响血小板数量和功能的疾病的诊断和治疗具有深远的意义。
Platelets are anuclear cytoplasmic fragments essential for blood clotting and wound healing. Despite much speculation, the factors determining their life span in the circulation are unknown. We show here that an intrinsic program for apoptosis, controls platelet survival and dictates their life span. Pro-survival Bcl-X-L constrains the pro-apoptotic activity of Bak to maintain platelet survival, but as Bcl-X-L degrades, aged platelets are primed for cell death. Genetic ablation or pharmacological inactivation of Bcl-X-L reduces platelet half-life and causes thrombocytopenia in a dose-dependent manner. Deletion of Bak corrects these defects, and platelets from Bak-deficient mice live longer than normal. Thus, platelets are, by default, genetically programmed to die by apoptosis. The antagonistic balance between Bcl-X-L and Bak constitutes a molecular clock that determines platelet life span: this represents an important paradigm for cellular homeostasis, and has profound implications for the diagnosis and treatment of disorders that affect platelet number and function.