PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • CCAAT-Binding Factor / metabolism*
  • COS Cells
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Chlorocebus 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 Serine-Threonine Kinases / metabolism*
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Deletion
  • p300-CBP Transcription Factors / chemistry
  • p300-CBP Transcription Factors / metabolism*

Substances

  • CBFB protein, human
  • CCAAT-Binding Factor
  • Carrier Proteins
  • Core Binding Factor Alpha 2 Subunit
  • Core Binding Factor beta Subunit
  • DNA Primers
  • Multiprotein Complexes
  • RUNX1 protein, human
  • Recombinant Proteins
  • p300-CBP Transcription Factors
  • HIPK2 protein, human
  • Protein Serine-Threonine Kinases