title: SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function.
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.
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors: Weina
authors: W
authors: Zhao
authors: Erin
authors: E
authors: Breese
authors: Allison
authors: A
authors: Bowers
authors: Jonathan
authors: J
authors: Hoggatt
authors: Louis M
authors: LM
authors: Pelus
authors: Hal E
authors: HE
authors: Broxmeyer
authors: Mark
authors: M
authors: Goebl
authors: Maureen A
authors: MA
authors: Harrington
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D056913:Mediator Complex Subunit 1 / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D051996:Transcription Factor RelA / Q000378:metabolism*; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D046912:Multiprotein Complexes; C498143:RELA protein, human; C493527:SIMPL protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha
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