Anamorsin, anti-apoptotic molecule, and hematopoiesis

许多生长因子和细胞因子可阻止细胞凋亡。通过基因表达克隆的方法，我们发现了一个新的抗凋亡分子Anamorsin，它与Down的凋亡调控分子如Bcl2家族、Caspase家族或信号转导分子没有任何同源性。Anamorsin在因子依赖的造血细胞系中的表达完全依赖于生长因子如白介素3、干细胞因子和血小板生成素的刺激，强制表达Anamorsin在体外可抵抗生长因子剥夺所致的细胞凋亡。此外，Anamorsin在体内被发现是一种抗凋亡分子，因为Anamorsin-/-小鼠由于胎儿肝脏(FL)的最终造血缺陷而在妊娠晚期死亡。尽管这些小鼠FL中的造血干/祖细胞数量没有减少，但髓系，特别是红系集落的形成对细胞因子的反应被严重破坏。此外，Anamorsin-/-红系细胞在终末成熟过程中启动了细胞凋亡。关于Anamorsin介导的细胞存活机制，基因芯片分析显示，在Anamorsin-/-小鼠FL中，Bclxl和JAK2的表达严重受损。因此，Anamorsin被认为是造血所必需的分子，它介导了各种细胞因子的抗凋亡作用。

Many growth factors and cytokines prevent apoptosis. Using an expression cloning method, we identified a novel antiapoptotic molecule named Anamorsin, which does not show any homology to Down apoptosis regulatory molecules such as Bcl-2 family, caspase family, or signal transduction molecules. The expression of Anamorsin was completely dependent on stimulation with growth factors, such as interleukin 3, stem cell factor, and thrombopoietin in factor-dependent hematopoietic cell lines, and forced expression of Anamorsin conferred resistance to apoptosis caused by growth factor deprivation in vitro. Furthermore, Anamorsin was found to act as an antiapoptotic molecule in vivo because Anamorsin -/- mice die in late gestation due to defective definitive hematopoiesis in the fetal liver (FL). Although the number of hematopoietic stem/progenitor cells in the FL did not decrease in these mice, myeloid, and particularly erythroid colony formation in response to cytokines, was severely disrupted. Also, Anamorsin -/- erythroid cells initiated apoptosis during terminal maturation. As for the mechanism of Anamorsin-mediated cell survival, a microarray analysis revealed that the expression of Bcl-xL and Jak2 was severely impaired in the FL of Anamorsin -/- mice. Thus, Anamorsin is considered to be a necessary molecule for hematopoiesis that mediates antiapoptotic effects of various cytokies.