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Title: A study of the role of reversible SUMOylation on vitamin D receptor/retinoid X receptor mediated signalling
Author: Lee, Wai-Ping
ISNI:       0000 0004 2721 4981
Awarding Body: University of Ulster
Current Institution: Ulster University
Date of Award: 2011
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Vitamin D Receptor (VDR) and Retinoid X Receptor (RXR) a. are ligand-inducible transcription factors. The activities of VDR and RXR are regulated by various posttranslational modifications. SUMOylation is the covalent attachment of Small Ubiquitin-like MOdifier (SUMO) to a specific lysine residue of a target protein, and the process is reversible by the action of SENtrinlSUMO proteases (SENP). The objective of this thesis is to illustrate the impact of reversible SUMOylation on the VDRlRXR mediated signalling. Our current findings showed that overexpression of SENP 1 and SENP2 enhanced the transactivation activity of both receptors. Increased SENPl levels are correlated with an increased expression of endogenous vitamin D (l,25D) target gene CYP24Al. Conversely, CYP24Al was down regulated by si-RNA knockdown of SENPl in Caco-2 cells. Further investigation of the SUMOylation status of the receptors revealed that VDR appeared preferentially SUMOylated by SUM02, while RXRa. is SUMOylated by SUMOl, 2 and 3. The modification of RXRa. and VDR is facilitated by a SUMO E3 ligase PIAS4 [Protein Inhibitor of the Activated ~TAT (Signal Transducer and Activator of Transcription) 4]. Overexpression of PIAS4 caused a repression on RXRa. transactivation, and results suggested such an effect is dependent on the SUMO E3 ligase activity. Moreover, our data revealed that RXRa. has another SUMO acceptor site in additional to the reported SUMOylation site KI08. In summary, our findings suggest that reversible SUMOylation is a novel regulatory mechanism for VDR-mediated signalling, that possibly modulates through VDR and RXR transcriptional functions. Future study of the mechanisms involving SENP/PIAS will better elucidate the functions of VDR and RXRa. containing complexes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available