SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function.
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3632537?pdf=render |
| _version_ | 1818040979449446400 |
|---|---|
| author | Weina Zhao Erin Breese Allison Bowers Jonathan Hoggatt Louis M Pelus Hal E Broxmeyer Mark Goebl Maureen A Harrington |
| author_facet | Weina Zhao Erin Breese Allison Bowers Jonathan Hoggatt Louis M Pelus Hal E Broxmeyer Mark Goebl Maureen A Harrington |
| author_sort | Weina Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T08:23:08Z |
| format | Article |
| id | doaj.art-01ef05c992144dbb907500daabf107bc |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T08:23:08Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-01ef05c992144dbb907500daabf107bc2022-12-22T01:56:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0184e6112310.1371/journal.pone.0061123SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function.Weina ZhaoErin BreeseAllison BowersJonathan HoggattLouis M PelusHal E BroxmeyerMark GoeblMaureen A HarringtonSignificant 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.http://europepmc.org/articles/PMC3632537?pdf=render |
| spellingShingle | Weina Zhao Erin Breese Allison Bowers Jonathan Hoggatt Louis M Pelus Hal E Broxmeyer Mark Goebl Maureen A Harrington SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function. PLoS ONE |
| title | SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function. |
| title_full | SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function. |
| title_fullStr | SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function. |
| title_full_unstemmed | SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function. |
| title_short | SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function. |
| title_sort | simpl enhancement of tumor necrosis factor α dependent p65 med1 complex formation is required for mammalian hematopoietic stem and progenitor cell function |
| url | http://europepmc.org/articles/PMC3632537?pdf=render |
| work_keys_str_mv | AT weinazhao simplenhancementoftumornecrosisfactoradependentp65med1complexformationisrequiredformammalianhematopoieticstemandprogenitorcellfunction AT erinbreese simplenhancementoftumornecrosisfactoradependentp65med1complexformationisrequiredformammalianhematopoieticstemandprogenitorcellfunction AT allisonbowers simplenhancementoftumornecrosisfactoradependentp65med1complexformationisrequiredformammalianhematopoieticstemandprogenitorcellfunction AT jonathanhoggatt simplenhancementoftumornecrosisfactoradependentp65med1complexformationisrequiredformammalianhematopoieticstemandprogenitorcellfunction AT louismpelus simplenhancementoftumornecrosisfactoradependentp65med1complexformationisrequiredformammalianhematopoieticstemandprogenitorcellfunction AT halebroxmeyer simplenhancementoftumornecrosisfactoradependentp65med1complexformationisrequiredformammalianhematopoieticstemandprogenitorcellfunction AT markgoebl simplenhancementoftumornecrosisfactoradependentp65med1complexformationisrequiredformammalianhematopoieticstemandprogenitorcellfunction AT maureenaharrington simplenhancementoftumornecrosisfactoradependentp65med1complexformationisrequiredformammalianhematopoieticstemandprogenitorcellfunction |