Xu G, Kanezaki R, Toki T, Watanabe S, Takahashi Y, Terui K, Kitabayashi I, Ito E
1Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Japan.
Leukemia. 2006 Jun;20(6):1002-8. doi: 10.1038/sj.leu.2404223.
Mutations of the GATA1 gene on chromosome X have been found in almost all cases of transient myeloproliferative disorder and acute megakaryoblastic leukemia (AMKL) accompanying Down syndrome (DS). Although most GATA1 mutations lead to the expression of GATA1s lacking the N-terminal activation domain, we recently found two novel GATA1 proteins with defects in another N-terminal region. It has been suggested that loss of the N-terminal portion of GATA1 might interfere with physiological interactions with the critical megakaryocytic transcription factor RUNX1, and this would imply that GATA1s is not able to interact properly with RUNX1. However, the interaction domain of GATA1 remains controversial. In this study, we show that GATA1 binds to RUNX1 through its zinc-finger domains, and that the C-finger is indispensable for synergy with RUNX1. All of the patient-specific GATA1 mutants interacted efficiently with RUNX1 and retained their ability to act synergistically with RUNX1 on the megakaryocytic GP1balpha promoter, whereas the levels of transcriptional activities were diverse among the mutants. Thus, our data indicate that physical interaction and synergy between GATA1 and RUNX1 are retained in DS-AMKL, although it is still possible that increased RUNX1 activity plays a role in the development of leukemia in DS.
在几乎所有唐氏综合征（DS）伴发的暂时性骨髓增殖性疾病和急性巨核细胞白血病（AMKL）病例中，均发现了X染色体上GATA1基因的突变。尽管大多数GATA1突变会导致缺乏N端激活域的GATA1s的表达，但我们最近发现了另外两种在另一个N端区域存在缺陷的新型GATA1蛋白。有人提出，GATA1 N端部分的缺失可能会干扰与关键巨核细胞转录因子RUNX1的生理相互作用，这意味着GATA1s无法与RUNX1正常相互作用。然而，GATA1的相互作用结构域仍存在争议。在本研究中，我们表明GATA1通过其锌指结构域与RUNX1结合，并且C指对于与RUNX1协同作用是不可或缺的。所有患者特异性的GATA1突变体均与RUNX1有效相互作用，并保留了在巨核细胞GP1balpha启动子上与RUNX1协同作用的能力，尽管突变体之间的转录活性水平各不相同。因此，我们的数据表明，GATA1与RUNX1之间的物理相互作用和协同作用在DS-AMKL中得以保留，尽管RUNX1活性增加仍有可能在DS白血病的发生中起作用。
