Direct binding of pRb/E2F-2 to GATA-1 regulates maturation and terminal cell division during erythropoiesis.
Direct binding of pRb/E2F-2 to GATA-1 regulates maturation and terminal cell division during erythropoiesis.
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DOI：
10.1371/journal.pbio.1000123
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发表时间：
2009-06-09
期刊：
影响因子：
9.8
通讯作者：
Chretien S
中科院分区：
文献类型：
--
作者：
Kadri Z;Shimizu R;Ohneda O;Maouche-Chretien L;Gisselbrecht S;Yamamoto M;Romeo PH;Leboulch P;Chretien S
细胞分化通常与细胞周期停滞相结合。在这里，我们证明红系转录因子 GATA-1 与视网膜母细胞瘤蛋白和 pRb/E2F 转录因子复合物的直接结合对于红细胞的形成至关重要。随着细胞最终分化，细胞增殖如何消退仍然是一个谜，尽管这种现象对于多细胞生物的存在至关重要。在这里，我们发现红细胞生成的主转录因子 GATA-1 与视网膜母细胞瘤蛋白 (pRb) 和 E2F-2 形成三复合物。这种相互作用需要一个 LXCXE 基序，该基序在 GATA-1 直向同源物中是进化保守的，但在其他 GATA 家族成员中不存在。 GATA-1/pRb/E2F-2 复合物的形成阻碍细胞增殖并引导红系前体细胞走向终末分化。该过程可在体外被 FOG-1 破坏，FOG-1 取代 GATA-1 中的 pRb/E2F-2。无法结合 pRb 的 GATA-1 突变体无法抑制细胞增殖，并导致小鼠胚胎因贫血而死亡。这些发现澄清了先前怀疑的 pRb 在红细胞生成过程中的细胞自主作用，并可能为与 GATA-1 突变相关的几种小鼠表型和人类疾病提供统一的分子机制。红细胞的产生或红细胞生成是通过增殖和分化的紧密耦合进行的。可识别的最早的红系祖细胞具有残余干细胞特征，因为它能够自我更新和分化。每个祖细胞产生超过 10,000 个细胞，包括次生祖细胞。然而，在下一阶段的分化过程中，这种更新能力大部分丧失，并且终末红系分化通过由单个有丝分裂分隔的几个阶段逐步进行。转录因子 GATA-1 对于红细胞分化至关重要，因为它诱导所有已知的红细胞特异性基因的表达。在这里，我们证明 GATA-1 直接与细胞分裂过程中的核心蛋白质相互作用：视网膜母细胞瘤蛋白 pRb 和转录因子 E2F。具体来说，E2F 在参与 GATA-1/pRb/E2F 三复合物后变得失活。另一种红细胞转录因子，称为 FOG-1，在体外与 GATA-1 结合后能够从该复合物中取代 pRb/E2F。我们假设释放的 pRb/E2F 可以成为后续调节的目标，最终释放游离的 E2F，从而触发细胞分裂。这种新途径的生理作用已通过转基因小鼠实验得到证实，GATA-1突变体无法结合pRb/E2F，从而导致胚胎因贫血而死亡。
Cell differentiation is often coupled with cell cycle arrest. Here, we show that direct binding of the erythroid transcription factor GATA-1 to the retinoblastoma protein and the pRb/E2F transcription factor complex is critical for red blood cell formation. How cell proliferation subsides as cells terminally differentiate remains largely enigmatic, although this phenomenon is central to the existence of multicellular organisms. Here, we show that GATA-1, the master transcription factor of erythropoiesis, forms a tricomplex with the retinoblastoma protein (pRb) and E2F-2. This interaction requires a LXCXE motif that is evolutionary conserved among GATA-1 orthologs yet absent from the other GATA family members. GATA-1/pRb/E2F-2 complex formation stalls cell proliferation and steers erythroid precursors towards terminal differentiation. This process can be disrupted in vitro by FOG-1, which displaces pRb/E2F-2 from GATA-1. A GATA-1 mutant unable to bind pRb fails to inhibit cell proliferation and results in mouse embryonic lethality by anemia. These findings clarify the previously suspected cell-autonomous role of pRb during erythropoiesis and may provide a unifying molecular mechanism for several mouse phenotypes and human diseases associated with GATA-1 mutations. Red blood cell production, or erythropoiesis, proceeds by a tight coupling of proliferation and differentiation. The earliest erythroid progenitor identifiable possesses remnant stem cell characteristics as it both self-renews and differentiates. Each progenitor gives rise to more than 10,000 cells, including secondary progenitors. Yet, during the next stage of differentiation, much of this renewal capability is lost, and terminal erythroid differentiation progresses in a stepwise manner through several stages separated by a single mitosis. The transcription factor GATA-1 is essential for erythroid differentiation because it induces the expression of all the known erythroid-specific genes. Here, we show that GATA-1 directly interacts with proteins that are central to the process of cell division: the retinoblastoma protein pRb and the transcription factor E2F. Specifically, E2F becomes inactivate after engaging in a GATA-1/pRb/E2F tricomplex. Another erythroid transcription factor, termed FOG-1, is able to displace pRb/E2F from this complex in vitro upon binding to GATA-1. We hypothesize that the liberated pRb/E2F can then be the target of subsequent regulation to ultimately release free E2F, which triggers cell division. The physiological role of this new pathway is evidenced by transgenic mouse experiments with GATA-1 mutants unable to bind pRb/E2F, which result in embryonic lethality by anemia.
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