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UltraRapid communication : nuclear factor-kappaB and cAMP response element binding protein mediate opposite

Illi, Puri, Morgante

    Circulation Research
    |June 24, 2000
    PubMed

    Insights

    Cyclic AMP response element-binding protein (CREB) and nuclear factor-kappaB (NF-kappaB) signaling pathways, involving histone acetyltransferases, oppositely regulate the vascular endothelial growth factor receptor Flk-1/KDR promoter, impacting angiogenesis.

    Area of Science:

    • Molecular Biology
    • Cell Signaling
    • Gene Regulation

    Background:

    • Vascular endothelial growth factor receptor (VEGFR) Flk-1/KDR is crucial during development but downregulated in adults.
    • Molecular mechanisms controlling Flk-1/KDR expression remain largely uncharacterized.

    Purpose of the Study:

    • To elucidate the molecular mechanisms governing Flk-1/KDR gene promoter activity.
    • To investigate the roles of transcription factors CREB and NF-kappaB in regulating Flk-1/KDR expression.

    Main Methods:

    • Analysis of transcription factor binding to the Flk-1/KDR promoter.
    • Functional studies using promoter activity assays.
    • Site-specific mutagenesis and investigation of histone acetyltransferases (HATs).

    Main Results:

    • CREB and NF-kappaB bind to specific sequences in the Flk-1/KDR promoter.
    • cAMP represses Flk-1/KDR promoter activity, while tumor necrosis factor-alpha (NF-kappaB activator) stimulates it.
    • HATs and p65/RelA significantly increase promoter activity; cAMP inhibition is reversed by HATs and abolished by CREB element mutation, while NF-kappaB element mutation affects NF-kappaB and HAT responsiveness.

    Conclusions:

    • Opposing signaling pathways involving NF-kappaB and CREB, dependent on HATs, control Flk-1/KDR promoter activity.
    • These findings provide insights into the transcriptional regulation of angiogenesis-related genes.

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