HIPK2介导的RUNX1和p300的PEBP2-β/CBF-β依赖性磷酸化：对白血病发生的影响
PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis.
作者信息
Wee Hee-Jun, Voon Dominic Chih-Cheng, Bae Suk-Chul, Ito Yoshiaki
机构信息
Genomics and Genetics Division, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Proteos, Singapore.
出版信息
Blood. 2008 Nov 1;112(9):3777-87. doi: 10.1182/blood-2008-01-134122. Epub 2008 Aug 11.
Abstract
The heterodimeric transcription factor RUNX1/PEBP2-beta (also known as AML1/CBF-beta) is essential for definitive hematopoiesis. Here, we show that interaction with PEBP2-beta leads to the phosphorylation of RUNX1, which in turn induces p300 phosphorylation. This is mediated by homeodomain interacting kinase 2 (HIPK2), targeting Ser(249), Ser(273), and Thr(276) in RUNX1, in a manner that is also dependent on the RUNX1 PY motif. Importantly, we observed the in vitro disruption of this phosphorylation cascade by multiple leukemogenic genetic defects targeting RUNX1/CBFB. In particular, the oncogenic protein PEBP2-beta-SMMHC prevents RUNX1/p300 phosphorylation by sequestering HIPK2 to mislocalized RUNX1/beta-SMMHC complexes. Therefore, phosphorylation of RUNX1 appears a critical step in its association with and phosphorylation of p300, and its disruption may be a common theme in RUNX1-associated leukemogenesis.
摘要
异二聚体转录因子RUNX1/PEBP2-β（也称为AML1/CBF-β）对于确定性造血至关重要。在此，我们表明与PEBP2-β的相互作用导致RUNX1磷酸化，进而诱导p300磷酸化。这是由同源结构域相互作用激酶2（HIPK2）介导的，它靶向RUNX1中的Ser(249)、Ser(273)和Thr(276)，其方式也依赖于RUNX1 PY基序。重要的是，我们观察到针对RUNX1/CBFB的多种白血病致病变异在体外破坏了这种磷酸化级联反应。特别是，致癌蛋白PEBP2-β-SMMHC通过将HIPK2隔离到错误定位的RUNX1/β-SMMHC复合物中，阻止了RUNX1/p300磷酸化。因此，RUNX1磷酸化似乎是其与p300结合和磷酸化的关键步骤，其破坏可能是RUNX1相关白血病发生的一个共同特征。
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本文引用的文献
1
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Adv Cancer Res. 2008;99:33-76. doi: 10.1016/S0065-230X(07)99002-8.
2
Runx1 protects hematopoietic stem/progenitor cells from oncogenic insult.Runx1保护造血干/祖细胞免受致癌损伤。
Stem Cells. 2007 Dec;25(12):2976-86. doi: 10.1634/stemcells.2007-0061. Epub 2007 Sep 6.
3
Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription.急性髓系白血病和骨髓增生异常综合征中HIPK2基因的突变会损害AML1和p53介导的转录。
Oncogene. 2007 Nov 8;26(51):7231-9. doi: 10.1038/sj.onc.1210523. Epub 2007 May 28.
4
HIPK2: a versatile switchboard regulating the transcription machinery and cell death.HIPK2：调控转录机制与细胞死亡的多功能枢纽
Cell Cycle. 2007 Jan 15;6(2):139-43. doi: 10.4161/cc.6.2.3788. Epub 2007 Jan 29.
5
Concurrent transcriptional deregulation of AML1/RUNX1 and GATA factors by the AML1-TRPS1 chimeric gene in t(8;21)(q24;q22) acute myeloid leukemia.在t(8;21)(q24;q22)急性髓系白血病中，AML1-TRPS1嵌合基因对AML1/RUNX1和GATA因子的同时转录失调。
Blood. 2007 May 1;109(9):4023-7. doi: 10.1182/blood-2006-01-031781. Epub 2007 Jan 23.
6
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Mol Cell Biol. 2006 Oct;26(20):7420-9. doi: 10.1128/MCB.00597-06. Epub 2006 Aug 5.
7
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8
Overlapping roles for homeodomain-interacting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals.同源结构域相互作用蛋白激酶Hipk1和Hipk2在介导细胞生长以响应形态发生信号和基因毒性信号过程中的重叠作用。
Mol Cell Biol. 2006 Apr;26(7):2758-71. doi: 10.1128/MCB.26.7.2758-2771.2006.
9
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10
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