Anamorsin, anti-apoptotic molecule, and hematopoiesis

许多生长因子和细胞因子阻止细胞凋亡。利用表达克隆的方法，我们鉴定了一种新的抗凋亡分子Anamorsin，它与Down凋亡调控分子如Bcl-2家族、caspase家族或信号转导分子没有任何同源性。Anamorsin的表达完全依赖于生长因子的刺激，例如因子依赖性造血细胞系中的白细胞介素3、干细胞因子和血小板生成素，并且Anamorsin的强制表达赋予对体外生长因子剥夺引起的细胞凋亡的抗性。此外，发现Anamorsin在体内充当抗凋亡分子，因为Anamorsin -/-小鼠由于胎肝（FL）中有缺陷的确定性造血而在妊娠晚期死亡。尽管这些小鼠FL中造血干/祖细胞的数量没有减少，但响应于细胞因子的髓系，特别是红系集落形成被严重破坏。此外，Anamorsin -/-红系细胞在终末成熟期间启动凋亡。至于Anamorsin介导的细胞存活的机制，微阵列分析显示Bcl-xL和Jak 2的表达在Anamorsin -/-小鼠的FL中严重受损。因此，Anamorsin被认为是造血的必要分子，其介导各种细胞的抗凋亡作用。

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.