气候变化领域集成服务门户(CCPortal): Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth

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DOI	10.1073/pnas.1922864118
	Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth
	Lee Y.-L.; Ito K.; Pi W.-C.; Lin I.-H.; Chu C.-S.; Malik S.; Cheng I.-H.; Chen W.-Y.; Roeder R.G.
发表日期	2021
ISSN	00278424
卷号	118 期号:6
英文摘要	The chimeric transcription factor E2A-PBX1, containing the N-terminal activation domains of E2A fused to the C-terminal DNA-binding domain of PBX1, results in 5% of pediatric acute lymphoblastic leukemias (ALL). We recently have reported a mechanism for RUNX1-dependent recruitment of E2A-PBX1 to chromatin in pre-B leukemic cells; but the subsequent E2A-PBX1 functions through various coactivators and the general transcriptional machinery remain unclear. The Mediator complex plays a critical role in cell-specific gene activation by serving as a key coactivator for gene-specific transcription factors that facilitates their function through the RNA polymerase II transcriptional machinery, but whether Mediator contributes to aberrant expression of E2A-PBX1 target genes remains largely unexplored. Here we show that Mediator interacts directly with E2A-PBX1 through an interaction of the MED1 subunit with an E2A activation domain. Results of MED1 depletion by CRISPR/Cas9 further indicate that MED1 is specifically required for E2APBX1-dependent gene activation and leukemic cell growth. Integrated transcriptome and cistrome analyses identify pre-B cell receptor and cell cycle regulatory genes as direct cotargets of MED1 and E2A-PBX1. Notably, complementary biochemical analyses also demonstrate that recruitment of E2A-PBX1 to a target DNA template involves a direct interaction with DNA-bound RUNX1 that can be further stabilized by EBF1. These findings suggest that E2A-PBX1 interactions with RUNX1 and MED1/Mediator are of functional importance for both gene-specific transcriptional activation and maintenance of E2A-PBX1-driven leukemia. The MED1 dependency for E2A-PBX1-mediated gene activation and leukemogenesis may provide a potential therapeutic opportunity by targeting MED1 in E2A-PBX1+ pre-B leukemia. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	E2A-PBX1 leukemia; EBF1; MED1; Mediator; RUNX1
语种	英语
scopus关键词	mediator complex; mediator subunit MED1; pre B cell leukemia transcription factor 1; pre B cell receptor; transcription factor; transcription factor E2A; transcription factor EBF1; transcription factor RUNX1; transcriptome; unclassified drug; Article; biochemical analysis; carcinogenicity; cell cycle progression; cell growth; cell survival; controlled study; CRISPR-CAS9 system; DNA binding; DNA template; gene activation; leukemia cell; leukemogenesis; priority journal; promoter region; protein depletion; protein DNA interaction; protein domain; protein expression; protein protein interaction; regulator gene; RNA analysis; transcription initiation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180704
作者单位	Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New York, NY 10065, United States; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, 112, Taiwan; Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan; Cancer Progression Research Center, National Yang-Ming University, Taipei, 112, Taiwan
推荐引用方式 GB/T 7714	Lee Y.-L.,Ito K.,Pi W.-C.,et al. Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth[J],2021,118(6).
APA	Lee Y.-L..,Ito K..,Pi W.-C..,Lin I.-H..,Chu C.-S..,...&Roeder R.G..(2021).Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth.Proceedings of the National Academy of Sciences of the United States of America,118(6).
MLA	Lee Y.-L.,et al."Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth".Proceedings of the National Academy of Sciences of the United States of America 118.6(2021).