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STABILISING SUPPRESSOR OF CYTOKINE SIGNALLING 3 (SOCS3) EXPRESSION TO LIMIT NEO-INTIMAL HYPERPLASIA
  1. Kirsten MA Munro1,
  2. Jamie JL Williams1,
  3. David Sumpton2,
  4. Andrew H Baker1,
  5. Timothy M Palmer1
  1. 1Institute of Cardiovascular and Medical Sciences
  2. 2CRUK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

Abstract

SOCS3 is an inducible inhibitor of multiple pathways responsible for the neo-intimal hyperplasia (NIH) that results in failure of stenting and coronary artery bypass graft (CABG) reconstructive procedures. However the potential for SOCS3 to limit NIH is compromised by its rapid turnover by the proteasome following ubiquitylation. Our original hypothesis is that stabilisation of endogenous SOCS3 by inhibiting its ubiquitylation has the potential to limit vascular inflammation and NIH. Consistent with this hypothesis, immunohistochemical analysis of human saphenous vein (HSV) sections derived from CABG patients revealed that while SOCS3 was expressed throughout the media, its expression within the neo-intima was reduced. We have shown that the L189A SOCS box mutant was ubiquitylated despite an inability to interact with the elongin B and C components of the E3 ligase machinery, suggesting that SOCS3 is not auto-ubiquitylated. Moreover, studies using a panel of SOCS3 truncation mutants revealed that SOCS3 is predominantly ubiquitylated within a C-terminal, 44 amino acid region in which Lys173 was the only potential target residue for ubiquitylation. Consistent with a role for this residue, ubiquitylation of a K173R-mutated SOCS3 mutant was markedly reduced versus WT SOCS3. K173 may therefore represent the critical site of ubiquitin attachment important for proteasomal turnover of SOCS3. Finally, we have pursued several approaches to identify the E3 ubiquitin ligase(s) and deubiquitinases that control SOCS3 sensitivity to proteasomal degradation. One of these has involved identification by mass spectrometry of proteins co-immunoprecipitating with SOCS3 and we will present the initial findings of this analysis.

  • CARDIAC PROCEDURES AND THERAPY

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