Notch signals inhibit the development of erythroid/megakaryocytic cells by suppressing GATA-1 activity through the induction of HES1
Notch signals inhibit the development of erythroid/megakaryocytic cells by suppressing GATA-1 activity through the induction of HES1
复制标题
DOI：
10.1074/jbc.m406788200
复制
发表时间：
2005-02-11
影响因子：
4.8
通讯作者：
Kanakura, Y
中科院分区：
文献类型：
--
作者：
Ishiko, E;Matsumura, I;Kanakura, Y
研究Notch信号对造血细胞红/巨核细胞分化的影响。细胞内Notch1或雌二醇诱导的Notch1/ER激活Notch信号可抑制红细胞/巨核细胞系K562中红细胞标记物糖蛋白A的表达。虽然模拟转染的K562细胞在TPA的作用下发生了巨核细胞分化，但雌二醇激活的Notch1/ER在TPA处理过程中诱导了细胞凋亡，并伴有抗凋亡分子Bcl-XL的表达降低。即使过度表达Bcl-XL可阻止细胞凋亡，激活的Notch信号仍可抑制tpa诱导的巨核细胞分化。在这一机制中，Notch1/重组信号结合蛋白j -kappa诱导HES1而非HES5抑制红/巨核细胞谱系特异性转录因子GATA-1的功能。虽然HES1在凝胶转移和染色质免疫沉淀试验中不影响GATA-1的DNA结合活性，但它直接结合GATA-1并从GATA-1中解离一个关键的转录辅助因子p300。此外，在集落实验中，过表达HES1抑制红细胞和巨核细胞的发育。此外，NIH3T3细胞上表达的Notch配体Jagged1抑制共培养Lin(-)Sca-1（+）造血干细胞/祖细胞的红细胞和巨核细胞的发育。这些结果表明，Notch1通过HES1抑制GATA-1活性来抑制红/巨核细胞的发育。
The effects of Notch signals on the erythroid/ imegakaryocytic differentiation of hematopoietic cells were examined. Activation of Notch signals by the intracellular Notch1 or an estradiol-inducible form of Notch1/ER suppressed the expression of the erythroid marker glycophorin A in an erythroid/megakaryocytic cell line K562. Although Mock-transfected K562 cells underwent megakaryocytic differentiation in response to '12-O-tetradecanoylphorbol-13-acetate (TPA), estradiol-activated Notch1/ER induced apoptosis during TPA treatment in the transfectant, which was accompanied by the reduced expression of an antiapoptotic molecule Bcl-XL. Even when apoptosis was prevented by the overexpression of Bcl-XL, activated Notch signals still inhibited TPA-induced megakaryocytic differentiation. As for this mechanism, Notch1/recombination signal binding protein J-kappa-induced HES1 but not HES5 was found to inhibit the function of an erythroid/megakaryocytic lineage-specific transcription factor GATA-1. Although HES1 did not affect the DNA binding activity of GATA-1 in gel shift and chromatin immunoprecipitation assays, it directly bound to GATA-1 and dissociated a critical transcriptional cofactor, p300, from GATA-1. Furthermore, overexpressed HES1 inhibited the development of erythroid and megakaryocytic cells in colony assays. Also, the Notch ligand Jagged1 expressed on NIH3T3 cells suppressed the development of erythroid and megakaryocytic cells from cocultured Lin(-)Sca-1(+) hematopoietic stem/progenitor cells. These results suggest that Notch1 inhibits the development of erythroid/ megakaryocytic cells by suppressing GATA-1 activity through HES1.