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WT1 和其转录共激活因子 BASP1 改变了已建立的血细胞系的分化途径。

WT1 and its transcriptional cofactor BASP1 redirect the differentiation pathway of an established blood cell line.

机构信息

Faculty of Life Sciences, The Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

出版信息

Biochem J. 2011 Apr 1;435(1):113-25. doi: 10.1042/BJ20101734.

DOI:10.1042/BJ20101734
PMID:21269271
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3062854/
Abstract

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.

摘要

Wilms 瘤抑制因子 WT1（Wilms 瘤 1）是一种转录调节剂，在器官发生中起着核心作用，并且在几种儿童和成人生殖细胞肿瘤中发生突变或异常表达。我们之前确定 BASP1（脑酸溶性蛋白 1）为 WT1 辅助因子，可抑制 WT1 的转录激活功能。在本研究中，我们分析了 WT1 和 BASP1 在髓性白血病 K562 细胞中基因表达调控中的动态关系。我们的研究结果表明，BASP1 是 WT1 的重要调节因子，可募集到 WT1 结合位点，并抑制几个 WT1 靶基因的 WT1 介导的转录激活。我们发现 WT1 和 BASP1 可以在佛波酯 PMA 诱导后改变 K562 细胞的分化程序，使其向非血细胞类型分化。WT1 和 BASP1 共同诱导 K562 细胞向神经元样形态分化，表现出广泛的分支，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，即细胞对神经递质 ATP 做出反应。总之，本研究的结果表明，WT1 和 BASP1 可以改变已建立的血细胞系的谱系潜能，使其向具有神经元特征的细胞分化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/2b4447520831/bic945i008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/47cf9db85f8f/bic945i001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/e481a9db81c4/bic945i002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/372b3c5f723f/bic945i003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/0a027cb56fd4/bic945i004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/2b4447520831/bic945i008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/47cf9db85f8f/bic945i001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/e481a9db81c4/bic945i002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/372b3c5f723f/bic945i003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/0a027cb56fd4/bic945i004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83d7/3062854/2b4447520831/bic945i008.jpg

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Mol Cell. 2010 Jan 29;37(2):159-71. doi: 10.1016/j.molcel.2009.12.023.
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The role of synapsins in neuronal development.突触结合蛋白在神经元发育中的作用。
Cell Mol Life Sci. 2010 May;67(9):1383-96. doi: 10.1007/s00018-009-0227-8. Epub 2009 Dec 25.
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An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1.一项综合基因组筛选将Wnt信号通路确定为WT1的主要靶点。
在婴儿急性髓细胞白血病中激活了 B 细胞发育基因调控网络。
PLoS One. 2021 Nov 18;16(11):e0259197. doi: 10.1371/journal.pone.0259197. eCollection 2021.
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Cholesterol is required for transcriptional repression by BASP1.胆固醇是 BASP1 转录抑制所必需的。
Proc Natl Acad Sci U S A. 2021 Jul 20;118(29). doi: 10.1073/pnas.2101671118.
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Temporal transcriptome analysis of neuronal commitment reveals the preeminent role of the divergent lncRNA biotype and a critical candidate gene during differentiation.神经元定向分化的时间转录组分析揭示了差异lncRNA生物型和一个关键候选基因在分化过程中的卓越作用。
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