Erythroid expansion mediated by the Gfi-1B zinc finger protein: role in normal hematopoiesis
Erythroid expansion mediated by the Gfi-1B zinc finger protein: role in normal hematopoiesis
复制标题
DOI：
10.1182/blood-2002-01-0182
复制
发表时间：
2002-10-15
期刊：
影响因子：
20.3
通讯作者：
Iwama, A
中科院分区：
文献类型：
--
作者：
Osawa, M;Yamaguchi, T;Iwama, A
在寻找造血干细胞中表达的基因时，我们发现Gfi-1B（生长因子独立-1B）的表达高度局限于造血干细胞、成红细胞和巨核细胞。 Gfi-1 和 Gfi-1B 是锌指蛋白，具有高度保守的 SNAG 和 6 个锌指结构域。 Gfi-1 已被定性为与小鼠淋巴恶性肿瘤有关的癌基因。相反，Gfi-1B 在造血中的作用尚未得到很好的表征。在这项研究中，我们分析了它在人类造血中的功能。 Gfi-1B在人CD34(+)造血祖细胞中的强制表达以不依赖促红细胞生成素的方式诱导成红细胞急剧扩增。 Gfi-1B 的表达并不促进红细胞定型，但增强了未成熟红细胞的增殖。然而，由外源性 Gfi-1B 扩增的成红细胞未能分化超出原红细胞阶段，并表现出大量凋亡。 Gfi-1 B 的这些生物学效应是通过其锌指结构域介导的，而不是通过 SNAG 或非锌指结构域介导的。有红细胞的增殖与 GATA-2 的持续表达相关，但与 GATA-1 无关，表明 Gfi-1B 和 GATA 家族调节因子之间存在潜在联系。重要的是，Gfi-1B 调节转录的功能取决于启动子背景。此外，人工启动子的转录激活是通过其锌指结构域介导的。这些发现确立了 Gfi-1 B 作为一种新型红系调节剂，并揭示了它通过调节红系特异性基因表达来具体参与红系细胞生长的调节。
In the search for genes expressed in hematopoietic stem cells, we identified that the expression of Gfi-1B (growth factor independence-1B) is highly restricted to hematopoietic stem cells, erythroblasts, and megakaryocytes. Gfi-1 and Gfi-1B are zinc finger proteins that share highly conserved SNAG and 6 zinc finger domains. Gfi-1 has been characterized as an oncogene involved in lymphoid malignancies in mice. In contrast, role of Gfi-1B in hematopoiesis has not been well characterized. In this study, we analyzed its function in human hematopoiesis. Enforced expression of Gfi-1B in human CD34(+) hematopoietic progenitors induced a drastic expansion of erythroblasts in an erythropoietin-independent manner. Expression of Gfi-1B did not promote erythroid commitment, but enhanced proliferation of immature erythroblasts. Erythroblasts expanded by exogenous Gfi-1B, however, failed to differentiate beyond proerythroblast stage and showed massive apoptosis. These biologic effects of Gfi-1 B were mediated through its zinc finger domain, but not by the SNAG or non-zinc finger domain. Proliferation of erythroblasts was associated with sustained expression of GATA-2 but not of GATA-1, indicating a potential link between Gfi-1B and GATA family regulators. Importantly, the function of Gfi-1B to modulate transcription was dependent on promoter context. In addition, activation of transcription of an artificial promoter was mediated through its zinc finger domain. These findings establish Gfi-1 B as a novel erythroid regulator and reveal its specific involvement in the regulation of erythroid cell growth through modulating erythroid-specific gene expression.