Project 1: Microrna regulation of the proto-oncogene PBF And Project 2: Recognition of previously undescribed ring domain residues required for BRCA1:BARD1 and RING1B:BMI1 ubiquitin ligase activity

[摘要] PROJECT 1: In thyroid cancers there have been independent observations of the overexpression of a relatively uncharacterised proto-oncogene, PBF, as well as the deregulation of microRNAs. Therefore, the aims of this investigation were to identify whether a selection of microRNAs can regulate PBF, altering its mRNA expression and protein levels. The most striking result indicated that hsa-miR-122-5p caused a significant decrease in PBF protein levels cells despite no change in PBF mRNA expression. Furthermore, hsa-miR-124-3p and hsa-miR-506-3p also negatively regulated PBF mRNA expression and protein levels; highlighting microRNAs do have the ability to regulate PBF. PROJECT 2: BRCA1:BARD1 and RING1B:BMI1 are type I RING-type E3 ubiquitin ligases required within the final stage of the ubiquitin pathway. The mechanism of E2-ubiquitin binding and locking remains elusive in type I RING-type E3 ubiquitin ligases despite being defined in type II RING-type E3 ubiquitin ligases. We identified the requirement of a conserved residue in BRCA1:BARD1 and RING1B:BMI1 for their ubiquitin ligase activity, with further investigations into RING1B:BMI1 ubiquitin sensitivity indicating the importance of a number of residues on ubiquitin’s surface for ubiquitin ligase activity. Modelling highlighted residues in RING1B:BMI1 and ubiquitin have the potential to interact via an E2-ubiquitin binding and locking mechanism.

[发布机构] University:University of Birmingham;Department:School of Clinical and Experiment Medicine, Department of Medicine and Medical Education

[关键词] R Medicine;RC Internal medicine;RC0254 Neoplasms. Tumors. Oncology (including Cancer)