SIMPL Enhancement of Tumor Necrosis Factor-α Dependent p65-MED1 Complex Formation Is Required for Mammalian Hematopoietic Stem and Progenitor Cell Function

Weina Zhao, Erin Breese, Allison Bowers, Jonathan Hoggatt, Louis Pelus, Hal Broxmeyer, Mark Goebl, Maureen Harrington

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Significant insight into the signaling pathways leading to activation of the Rel transcription factor family, collectively termed NF-κB, has been gained. Less well understood is how subsets of NF-κB-dependent genes are regulated in a signal specific manner. The SIMPL protein (signaling molecule that interacts with mouse pelle-like kinase) is required for full Tumor Necrosis Factor-α (TNFα) induced NF-κB activity. We show that SIMPL is required for steady-state hematopoiesis and the expression of a subset of TNFα induced genes whose products regulate hematopoietic cell activity. To gain insight into the mechanism through which SIMPL modulates gene expression we focused on the Tnf gene, an immune response regulator required for steady-state hematopoiesis. In response to TNFα SIMPL localizes to the Tnf gene promoter where it modulates the initiation of Tnf gene transcription. SIMPL binding partners identified by mass spectrometry include proteins involved in transcription and the interaction between SIMPL and MED1 was characterized in more detail. In response to TNFα, SIMPL is found in p65-MED1 complexes where SIMPL enhances p65/MED1/SIMPL complex formation. Together our results indicate that SIMPL functions as a TNFα-dependent p65 co-activator by facilitating the recruitment of MED1 to p65 containing transcriptional complexes to control the expression of a subset of TNFα-induced genes.

Original languageEnglish
Article numbere61123
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 22 2013

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tumor necrosis factors
Hematopoietic Stem Cells
Tumor Necrosis Factor-alpha
Genes
hematopoiesis
genes
Hematopoiesis
Transcription
transcription (genetics)
Gene expression
Mass spectrometry
hematopoietic stem cells
Mass Spectrometry
phosphotransferases (kinases)
Proteins
Transcription Factors
Phosphotransferases
transcription factors
proteins
Chemical activation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

SIMPL Enhancement of Tumor Necrosis Factor-α Dependent p65-MED1 Complex Formation Is Required for Mammalian Hematopoietic Stem and Progenitor Cell Function. / Zhao, Weina; Breese, Erin; Bowers, Allison; Hoggatt, Jonathan; Pelus, Louis; Broxmeyer, Hal; Goebl, Mark; Harrington, Maureen.

In: PLoS One, Vol. 8, No. 4, e61123, 22.04.2013.

Research output: Contribution to journalArticle

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