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PMID:18695000
| Citation |
Wee, HJ, Voon, DC, Bae, SC and Ito, Y (2008) PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. Blood 112:3777-87 |
|---|---|
| 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. |
| Links |
PubMed PMC2572802 Online version:10.1182/blood-2008-01-134122 |
| Keywords |
Animals; Base Sequence; CCAAT-Binding Factor/metabolism; COS Cells; Carrier Proteins/metabolism; Cell Line, Tumor; Cercopithecus aethiops; Core Binding Factor Alpha 2 Subunit/chemistry; Core Binding Factor Alpha 2 Subunit/genetics; Core Binding Factor Alpha 2 Subunit/metabolism; Core Binding Factor beta Subunit/chemistry; Core Binding Factor beta Subunit/metabolism; DNA Primers/genetics; Humans; K562 Cells; Leukemia/etiology; Leukemia/genetics; Leukemia/metabolism; Mice; Multiprotein Complexes; Mutagenesis, Site-Directed; Phosphorylation; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases/metabolism; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Sequence Deletion; p300-CBP Transcription Factors/chemistry; p300-CBP Transcription Factors/metabolism |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
|
enables |
GO:0004674: protein serine/threonine kinase activity |
ECO:0000269: experimental evidence used in manual assertion |
F |
Seeded From UniProt |
complete | |||
Notes
See also
References
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