Subnuclear targeting of Runx1 is required for synergistic activation of the myeloid specific M-CSF receptor promoter by PU.1

Xiangen Li, Diana Vradii, Soraya Gutierrez, Jane B. Lian, Andre J. Van Wijnen, Janet L. Stein, Gary S. Stein, Amjad Javed

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Many types of acute myelogenous leukemia involve chromosomal translocations that target the C-terminus of Runx1/AML1 transcription factor, a master regulator of hematopoiesis. The C-terminus of Runx1/AML1 that includes the nuclear matrix targeting signal (NMTS) is essential for embryonic development, hematopoiesis, and target gene regulation. During the onset and normal progression of hematopoiesis, several lineage-specific factors such as C/EBPα and PU.1 interact with Runx1 to regulate transcription combinatorially. Here we addressed the functional interplay between subnuclear targeting of Runx1 and gene activation during hematopoiesis. Point mutations were generated in the NMTS of the human Runx1 protein and tested for their effect on transcriptional cooperativity with C/EBPα and PU.1 at myeloid-specific promoters. We characterized five mutants that do not alter nuclear import, DNA binding or C/EBPα-dependent synergistic activation of the target gene promoters. However a critical tyrosine in the NMTS is required for subnuclear targeting and activation of the granulocyte-macrophage colony stimulating factor (GM-CSF) promoter. Furthermore, this point mutation is defective for transcriptional synergism with PU.1 on the macrophage colony stimulating factor (MCSF) receptor c-FMS promoter. Our results indicate that the NMTS region of Runx1 is required for functional interactions with PU.1. Taken together, our findings establish that subnuclear targeting of Runx1 is a critical component of myeloid-specific transcriptional control.

Original languageEnglish (US)
Pages (from-to)795-809
Number of pages15
JournalJournal of cellular biochemistry
Volume96
Issue number4
DOIs
StatePublished - Nov 1 2005

    Fingerprint

Keywords

  • AML1
  • Hematopoiesis
  • Leukemia
  • Nuclear matrix
  • Transcriptional regulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Li, X., Vradii, D., Gutierrez, S., Lian, J. B., Van Wijnen, A. J., Stein, J. L., Stein, G. S., & Javed, A. (2005). Subnuclear targeting of Runx1 is required for synergistic activation of the myeloid specific M-CSF receptor promoter by PU.1. Journal of cellular biochemistry, 96(4), 795-809. https://doi.org/10.1002/jcb.20548