LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.
LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.
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DOI：
10.1016/j.devcel.2009.09.005
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发表时间：
2009-10
影响因子：
11.8
通讯作者：
Pandolfi, Pier Paolo
中科院分区：
文献类型：
--
作者：
Maeda, Takahiro;Ito, Keisuke;Merghoub, Taha;Poliseno, Laura;Hobbs, Robin M.;Wang, Guocan;Dong, Lin;Maeda, Manarni;Dore, Louis C.;Zelent, Arthur;Luzzatto, Lucio;Teruya-Feldstein, Julie;Weiss, Mitchell J.;Pandolfi, Pier Paolo
GATA-1 依赖性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该过程至关重要。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，我们证明 POZ-Krüppel 家族转录因子 LRF（也称为 Zbtb7a/Pokemon）是 GATA1 的直接靶标，在红系终末分化过程中发挥重要的抗凋亡作用。我们发现，由于晚期成红细胞凋亡增加，Lrf 的缺失会导致胚胎致命性贫血。这种程序性细胞死亡不依赖于 Arf 和 p53，而是通过促凋亡因子 Bim 的上调介导。我们将 Lrf 确定为 Bim 转录的直接抑制因子。在这一机制的有力支持下，遗传性 Bim 缺失延迟了 Lrf 缺陷胚胎的致死率并挽救了其贫血表型。因此，我们的数据定义了有效红细胞生成的关键转录级联，GATA-1 通过 LRF 抑制 BIM 介导的细胞凋亡。
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 anti-apoptotic 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 up-regulation of the pro-apoptotic 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 defines a key transcriptional cascade for effective erythropoiesis, whereby GATA-1 suppresses BIM-mediated apoptosis via LRF.
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影响因子：
8
作者：
Davies, JM;Hawe, N;Zelent, A
通讯作者：
Zelent, A
影响因子：
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WEATHERALL, DJ