Maeda Takahiro, Ito Keisuke, Merghoub Taha, Poliseno Laura, Hobbs Robin M, Wang Guocan, Dong Lin, Maeda Manami, Dore Louis C, Zelent Arthur, Luzzatto Lucio, Teruya-Feldstein Julie, Weiss Mitchell J, Pandolfi Pier Paolo
Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Dev Cell. 2009 Oct;17(4):527-40. doi: 10.1016/j.devcel.2009.09.005.
GATA-1-dependent transcription is essential for erythroid differentiation and maturation. Suppression of programmed cell death is also thought to be critical for this process; however, the link between these two features of erythropoiesis has remained elusive. Here, we show that the POZ-Krüppel family transcription factor, LRF (also known as Zbtb7a/Pokemon), is a direct target of GATA1 and plays an essential antiapoptotic role during terminal erythroid differentiation. We find that loss of Lrf leads to lethal anemia in embryos, due to increased apoptosis of late-stage erythroblasts. This programmed cell death is Arf and p53 independent and is instead mediated by upregulation of the proapoptotic factor Bim. We identify Lrf as a direct repressor of Bim transcription. In strong support of this mechanism, genetic Bim loss delays the lethality of Lrf-deficient embryos and rescues their anemia phenotype. Thus, our data define a key transcriptional cascade for effective erythropoiesis, whereby GATA-1 suppresses BIM-mediated apoptosis via LRF.
GATA-1依赖的转录对于红细胞分化和成熟至关重要。抑制程序性细胞死亡也被认为对这一过程至关重要；然而，红细胞生成的这两个特征之间的联系仍然难以捉摸。在这里，我们表明POZ-Krüppel家族转录因子LRF（也称为Zbtb7a/ Pokemon）是GATA1的直接靶点，并在终末红细胞分化过程中发挥重要的抗凋亡作用。我们发现Lrf缺失会导致胚胎出现致命性贫血，这是由于晚期成红细胞凋亡增加所致。这种程序性细胞死亡不依赖于Arf和p53，而是由促凋亡因子Bim的上调介导的。我们确定Lrf是Bim转录的直接抑制因子。有力支持这一机制的是，基因敲除Bim可延迟Lrf缺陷胚胎的致死性并挽救其贫血表型。因此，我们的数据定义了一个有效的红细胞生成关键转录级联，即GATA-1通过LRF抑制BIM介导的细胞凋亡。
