Cross Talk between Retinoic Acid Signaling and Transcription Factor GATA-2
Cross Talk between Retinoic Acid Signaling and Transcription Factor GATA-2
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DOI：
10.1128/mcb.24.15.6824-6836.2004
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发表时间：
2004-08
影响因子：
5.3
通讯作者：
S. Tsuzuki;K. Kitajima;T. Nakano;A. Glasow;A. Zelent;T. Enver
中科院分区：
文献类型：
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作者：
S. Tsuzuki;K. Kitajima;T. Nakano;A. Glasow;A. Zelent;T. Enver
全反式维甲酸（RA）对正常造血祖细胞和急性髓系白血病细胞的分化有促进作用。加塔-2是一种在早期祖细胞中表达的转录因子，并参与造血干细胞和祖细胞命运的控制。我们已经研究了加塔和核激素受体途径通过直接蛋白质-蛋白质相互作用在功能上相关联的可能性。在这里，我们证明了在人髓系KG 1细胞中，RA受体α（RARα），造血细胞中表达的主要RAR，与加塔-2相关。这种结合是由加塔-2的锌指和RARα的DNA结合域介导的。这种相互作用的结果是，RARα与被加塔-2识别和结合的DNA位点相连，并且加塔-2的转录活性成为RA应答性的。GATA依赖性转录的RA响应性通过RARα的显性负性形式或不能与RARα相互作用的加塔-2突变体的表达而消除。RXRα的过表达抑制RARα与加塔-2-DNA复合物的结合，从而导致RARα对加塔-2活性的影响减弱。此外，在造血分化的胚胎干细胞模型中，RA对加塔-2依赖性造血集落形成的抑制为RA和加塔-2依赖性途径之间的功能性串扰提供了生物学证据。
ABSTRACT All-trans-retinoic acid (RA) stimulates differentiation of normal hematopoietic progenitors and acute myeloid leukemia cells. GATA-2 is a transcription factor expressed in early progenitor cells and implicated in the control of the fate of hematopoietic stem cells and progenitor cells. We have investigated the possibility that the GATA and nuclear hormone receptor pathways are functionally linked through direct protein-protein interaction. Here we demonstrate that in human myeloid KG1 cells, RA receptor alpha (RARα), the major RAR expressed in hematopoietic cells, associates with GATA-2. This association is mediated by the zinc fingers of GATA-2 and the DNA-binding domain of RARα. As a consequence of this interaction, RARα is tethered to the DNA sites that are recognized and bound by GATA-2, and the transcriptional activity of GATA-2 becomes RA responsive. The RA responsiveness of GATA-dependent transcription is eliminated by expression of either a dominant negative form of RARα or a GATA-2 mutant that fails to interact with RARα. Overexpression of RXRα inhibits RARα binding to the GATA-2-DNA complex, thus resulting in attenuation of the effects of RARα on GATA-2 activity. In addition, inhibition by RA of GATA-2-dependent hematopoietic colony formation in an embryonic stem cell model of hematopoietic differentiation provided biological evidence for functional cross talk between RA and GATA-2-dependent pathways.