WT1 and its transcriptional cofactor BASP1 redirect the differentiation pathway of an established blood cell line.
WT1 and its transcriptional cofactor BASP1 redirect the differentiation pathway of an established blood cell line.
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DOI：
10.1042/bj20101734
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发表时间：
2011-04-01
期刊：
影响因子：
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通讯作者：
Roberts SG
中科院分区：
文献类型：
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作者：
Goodfellow SJ;Rebello MR;Toska E;Zeef LA;Rudd SG;Medler KF;Roberts SG
Wilms肿瘤抑制因子WT 1（Wilms肿瘤1）是一种在器官发生中起核心作用的转录调节因子，在几种儿童和成人恶性肿瘤中突变或异常表达。我们以前确定BASP 1（脑酸溶性蛋白1）作为WT1的辅因子，抑制WT1的转录激活功能。在本研究中，我们分析了WT1和BASP 1在髓性白血病K562细胞基因表达调控中的动态变化。我们的研究结果表明，BASP1是一个重要的WT1的调节器，被招募到WT1结合位点，并抑制WT1介导的转录激活在几个WT1靶基因。我们发现，WT1和BASP 1可以转移K562细胞的分化程序，以非血细胞类型的诱导佛波醇酯PMA。WT1和BASP1协同诱导K562细胞分化为神经元样形态，表现出广泛的树枝化，以及参与神经突生长和突触形成的几个基因的表达。功能分析揭示了转录重编程和形态变化的相关性，因为细胞引起了对神经递质ATP的反应。总之，本研究的结果表明，WT1和BASP 1可以将已建立的血细胞系的谱系潜力转向具有神经元特征的细胞。
The Wilms' tumour suppressor WT1 (Wilms' tumour 1) is a transcriptional regulator that plays a central role in organogenesis, and is mutated or aberrantly expressed in several childhood and adult malignancies. We previously identified BASP1 (brain acid-soluble protein 1) as a WT1 cofactor that suppresses the transcriptional activation function of WT1. In the present study we have analysed the dynamic between WT1 and BASP1 in the regulation of gene expression in myelogenous leukaemia K562 cells. Our findings reveal that BASP1 is a significant regulator of WT1 that is recruited to WT1-binding sites and suppresses WT1-mediated transcriptional activation at several WT1 target genes. We find that WT1 and BASP1 can divert the differentiation programme of K562 cells to a non-blood cell type following induction by the phorbol ester PMA. WT1 and BASP1 co-operate to induce the differentiation of K562 cells to a neuronal-like morphology that exhibits extensive arborization, and the expression of several genes involved in neurite outgrowth and synapse formation. Functional analysis revealed the relevance of the transcriptional reprogramming and morphological changes, in that the cells elicited a response to the neurotransmitter ATP. Taken together, the results of the present study reveal that WT1 and BASP1 can divert the lineage potential of an established blood cell line towards a cell with neuronal characteristics.