Submitted January 18, 2008
Accepted July 27, 2008
PEBP2
/CBF-dependent phosphorylation of RUNX1 and p300 by HIPK2: Implications for leukemogenesis
Hee-Jun Wee, Dominic Chih-Cheng Voon, Suk-Chul Bae, and Yoshiaki Ito*
Genomics and Genetics Division, Institute of Molecular and Cell Biology, Singapore
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju, Korea, Republic of
Oncology Research Institute, Centre for Life Sciences, National University of Singapore, Singapore
* Corresponding author; email: itoy{at}imcb.a-star.edu.sg.
The heterodimeric transcription factor RUNX1/PEBP2
(also known as AML1/CBF) is essential for definitive hematopoiesis. Here, we show that interaction with PEBP2 leads to the phosphorylation of RUNX1, which in turn induces p300 phosphorylation. This is mediated by homeodomain interacting kinase 2 (HIPK2), targeting Ser249, Ser273 and Thr276 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/PEBP2. In particular, the oncogenic protein PEBP2-SMMHC prevents RUNX1/p300 phosphorylation by sequestering HIPK2 to mislocalised RUNX1/-SMMHC complexes. Therefore, phosphorylation of RUNX1 appears a critical step in its association with p300, and its disruption may be a common theme in RUNX1-associated leukemogenesis.
