Wee Hee-Jun, Voon Dominic Chih-Cheng, Bae Suk-Chul, Ito Yoshiaki
Genomics and Genetics Division, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Proteos, Singapore.
Blood. 2008 Nov 1;112(9):3777-87. doi: 10.1182/blood-2008-01-134122. Epub 2008 Aug 11.
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.
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。