Elevation of cyclic AMP in Jurkat T-cells provokes distinct transcriptional responses through the protein kinase A (PKA) and exchange protein activated by cyclic AMP (EPAC) pathways

Suzanne Fuld, Gillian Borland, S. J. Yarwood

    Research output: Contribution to journalArticle

    Abstract

    Elevating cyclic AMP with a combination of forskolin and IBMX (Fskn/IBMX) was found as the cause of G1 growth arrest in Jurkat T-cells, concomitant with an induction of the cyclin-dependent kinase inhibitor, p27Kip1. The protein kinase inhibitor H-89, which can discriminate between EPAC and PKA pathways, blocked the inhibition in cell growth and induction of p27Kip1, indicating an involvement of PKA, but not EPAC. The EPAC-specific cyclic AMP analogue, 8-CPT-2Me-cAMP was able to activate Rap1, but failed to induce growth arrest or induction p27Kip1. These results demonstrate that PKA, and not EPAC, mediates cyclic AMP-dependent growth arrest in Jurkat T-cells. To further investigate a role for EPAC in these cells, we carried out cDNA microarray analysis of cells stimulated with 8-CPT-2Me-cAMP. We identified separate groups of genes whose expression was either induced or repressed in response to 8-CPT-2Me-cAMP. This provides the first demonstration that EPAC can regulate gene expression, although it may not be involved in cell cycle control. Finally, we identify c-Jun as a transcription factor whose activity is specifically down-regulated following EPAC activation, but not PKA. The control of gene expression by cyclic AMP in Jurkat T-cells therefore requires input from the EPAC signalling cascade.

    Original languageEnglish
    Pages (from-to)161-173
    Number of pages13
    JournalExperimental Cell Research
    Volume309
    Issue number1
    DOIs
    Publication statusPublished - 10 Sep 2005

    Keywords

    • Cell Cycle
    • Cyclic AMP
    • Cyclic AMP-Dependent Protein Kinases
    • Cyclin-Dependent Kinase Inhibitor p27
    • Enzyme Inhibitors
    • G1 Phase
    • Guanine Nucleotide Exchange Factors
    • Humans
    • Jurkat Cells
    • Signal Transduction
    • Transcriptional Activation
    • Up-Regulation
    • rap1 GTP-Binding Proteins

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