Zhuang H, Niu Z, He T C, Patel S V, Wojchowski D M
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park 16802, USA.
J Biol Chem. 1995 Jun 16;270(24):14500-4. doi: 10.1074/jbc.270.24.14500.
Apoptosis, or programmed cell death (PCD), recently has emerged as an important homeostatic mechanism within several hematopoietic lineages. This process is subject to both positive and negative modulation by cytokines and within the erythroid lineage is inhibited by interleukin-3, stem cell factor, and erythropoietin (Epo). Through the expression of carboxyl-truncated Epo receptor mutants in FDC-P1 cells, a receptor form possessing 80 membrane-proximal cytoplasmic residues is shown to efficiently mediate Epo-dependent inhibition of PCD. This is in contrast to previous studies that attributed this activity to a distal carboxyl-terminal receptor subdomain (and/or heterodimerization of wild type Epo receptors with a truncated non-functional receptor form). Epo-dependent inhibition of PCD also is shown to be blocked by ectopic expression of kinase-deficient dominant-negative forms of Jak2 (Jak2 delta VIII and Jak2-829), further underlining a role of this membrane-proximal subdomain of the Epo receptor in the inhibition of PCD. To our knowledge, this comprises the first direct evidence for an essential role for a Jak tyrosine kinase (Jak2) in this apoptotic response pathway.
凋亡，即程序性细胞死亡（PCD），最近已成为多种造血谱系中的一种重要稳态机制。该过程受到细胞因子的正负调节，在红系谱系中，白细胞介素-3、干细胞因子和促红细胞生成素（Epo）可抑制其发生。通过在FDC-P1细胞中表达羧基截短的Epo受体突变体，发现一种具有80个膜近端胞质残基的受体形式可有效介导Epo依赖的PCD抑制作用。这与之前将该活性归因于远端羧基末端受体亚结构域（和/或野生型Epo受体与截短的无功能受体形式的异源二聚化）的研究形成对比。Epo依赖的PCD抑制作用还被Jak2的激酶缺陷型显性负性形式（Jak2 delta VIII和Jak2-829）的异位表达所阻断，这进一步强调了Epo受体的该膜近端亚结构域在抑制PCD中的作用。据我们所知，这是Jak酪氨酸激酶（Jak2）在该凋亡反应途径中起重要作用的首个直接证据。
