Gene interactions and pathways from curated databases and text-mining
Nature 2006, PMID: 16799563

An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis.

Yang, Fajun; Vought, Bryan W; Satterlee, John S; Walker, Amy K; Jim Sun, Z-Y; Watts, Jennifer L; DeBeaumont, Rosalie; Saito, R Mako; Hyberts, Sven G; Yang, Shaosong; Macol, Christine; Iyer, Lakshmanan; Tjian, Robert; van den Heuvel, Sander; Hart, Anne C; Wagner, Gerhard; Näär, Anders M

The sterol regulatory element binding protein (SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis. We previously demonstrated that human SREBPs bind the CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit activator-recruited co-factor (ARC)/Mediator co-activator complexes through unknown mechanisms. Here we show that SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes. Structural analysis of the SREBP-binding domain in ARC105 by NMR revealed a three-helix bundle with marked similarity to the CBP/p300 KIX domain. In contrast to SREBPs, the CREB and c-Myb activators do not bind the ARC105 KIX domain, although they interact with the CBP KIX domain, revealing a surprising specificity among structurally related activator-binding domains. The Caenorhabditis elegans SREBP homologue SBP-1 promotes fatty acid homeostasis by regulating the expression of lipogenic enzymes. We found that, like SBP-1, the C. elegans ARC105 homologue MDT-15 is required for fatty acid homeostasis, and show that both SBP-1 and MDT-15 control transcription of genes governing desaturation of stearic acid to oleic acid. Notably, dietary addition of oleic acid significantly rescued various defects of nematodes targeted with RNA interference against sbp-1 and mdt-15, including impaired intestinal fat storage, infertility, decreased size and slow locomotion, suggesting that regulation of oleic acid levels represents a physiologically critical function of SBP-1 and MDT-15. Taken together, our findings demonstrate that ARC105 is a key effector of SREBP-dependent gene regulation and control of lipid homeostasis in metazoans.

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Text Mining Data

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Manually curated Databases

  • IRef Biogrid Interaction: CREBBP — KMT2A (association, x-ray crystallography)
  • IRef Biogrid Interaction: CREBBP — MYB (association, x-ray crystallography)
  • IRef Biogrid Interaction: SREBF1 — CREBBP (direct interaction, pull down)
  • IRef Biogrid Interaction: SREBF1 — CREBBP (colocalization, imaging technique)
  • IRef Biogrid Interaction: CREBBP — CREB1 (association, x-ray crystallography)
  • IRef Biogrid Interaction: SREBF1 — MED15 (direct interaction, pull down)
  • IRef Biogrid Interaction: SREBF1 — MED15 (association, x-ray crystallography)
  • IRef Biogrid Interaction: SREBF1 — MED15 (colocalization, imaging technique)
  • IRef Biogrid Interaction: MED6 — SREBF1 (direct interaction, pull down)
  • IRef Biogrid Interaction: MED26 — SREBF1 (direct interaction, pull down)
  • IRef Biogrid Interaction: SREBF1 — MED24 (direct interaction, pull down)
  • IRef Biogrid Interaction: SREBF1 — MED12 (direct interaction, pull down)
  • IRef Biogrid Interaction: MED13 — SREBF1 (direct interaction, pull down)
  • IRef Biogrid Interaction: SREBF1 — MED23 (direct interaction, pull down)
  • IRef Biogrid Interaction: MED14 — SREBF1 (direct interaction, pull down)
  • IRef Biogrid Interaction: MED1 — SREBF1 (colocalization, imaging technique)
  • IRef Biogrid Interaction: MED1 — SREBF1 (direct interaction, pull down)
  • IRef Biogrid Interaction: SREBF1 — MED25 (direct interaction, pull down)
  • IRef Biogrid Interaction: CDK8 — SREBF1 (direct interaction, pull down)
  • IRef Biogrid Interaction: MED17 — SREBF1 (direct interaction, pull down)
  • IRef Biogrid Interaction: MED1 — THRA (direct interaction, pull down)
  • IRef Dip Interaction: CREBBP — MYB (physical association, pull down)
  • IRef Intact Interaction: MED15 — SREBF1 (physical association, classical fluorescence spectroscopy)
  • IRef Intact Interaction: MED15 — SREBF1 (physical association, pull down)
  • IRef Intact Interaction: MED15 — SREBF1 (physical association, anti tag coimmunoprecipitation)
  • IRef Intact Interaction: Complex of MED6-CREBBP-MED1-SREBF1-CDK8-MED15 (association, pull down)
  • IRef Intact Interaction: Complex of CREBBP-SREBF1-MED6-MED15-MED1-CDK8 (association, pull down)
  • IRef Intact Interaction: Complex of MED15-SREBF1 (association, pull down)
  • IRef Intact Interaction: Complex of MED15-SREBF1 (association, pull down)
  • IRef Intact Interaction: MED15 — CREB1 (physical association, pull down)
  • IRef Intact Interaction: MED1 — THRA (physical association, pull down)
  • IRef Intact Interaction: MED15 — MYB (physical association, pull down)
  • IRef Intact Interaction: Complex of MED1-CREBBP-SREBF2-MED6-CDK8-MED15 (association, pull down)
  • IRef Intact Interaction: Complex of MED15-SREBF2 (association, pull down)
In total, 34 gene pairs are associated to this article in curated databases