Endocrine Abstracts

The SOCS3 gene encodes an E3 ubiquitin ligase component that targets inflammatory cytokine receptor components for proteolytic degradation. Our research in this area is aimed at determining the molecular control of SOCS3 gene induction by cyclic AMP in vascular endothelial cells (VECs) as a new route for anti-inflammatory drug action. We found initially that cyclic AMP activates the guanine nucleotide exchange factor, EPAC1, to mobilise C/EBP transcription factors to induce SOCS3 expression in VECs. Maximal SOCS3 induction in response to cyclic AMP also requires activation of JNK and ERK MAP kinase signalling pathways, which target AP-1, STAT and SP3 transcription factors on the minimal SOCS3 promoter. ERK and JNK activation by cyclic AMP occurs through novel protein kinase C-dependent mechanisms, independently of EPAC1 and protein kinase A. We have also found that some of these mechanisms can also be activated by bioactive small molecules, including citrus-derived flavanoids, which target activation of SP3 transcription factors. Our future work in this area will be aimed at further identifying small molecule regulators (e.g. PDE4 inhibitors) of these novel signalling mechanisms in VECs.