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Characterisation of DRAM-1 in vitro and in vivo

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Disciplines
  • Biology
  • Medicine

Abstract

Autophagy is a cellular housekeeping process that drives the degradation of intracellular and extracellular components in the lysosomes. Defects in this process have been implicated with many diseases, among them cancer. Damage-Regulated Autophagy Modulator (DRAM-1) is a p53 target gene that has been shown to regulate autophagy, and it is believed to act as a tumour suppressor. In addition to the full-length transcript (splice variant 1) that has previously been characterised, multiple splice isoforms of DRAM-1 have been identified. The first part of this thesis focuses on the investigation of the properties of the DRAM-1 isoforms 1, 4 and 5. These isoforms are localised to different cellular compartments. DRAM-1 isoforms are highly specific regulators of autophagy. They neither mediate the turnover of long-lived proteins nor do they decrease enhanced intracellular reactive oxygen species (ROS). Although activation of DRAM-1 on its own does not promote cell death, it is required for effective p53-mediated cell death in vitro. The next step was to proceed to the characterisation of the cellular function of DRAM-1 in vivo. In the final part of the thesis, the role of DRAM-1 in mediating T cell activation was examined. In summary, these results contribute to the understanding of how autophagy is regulated by DRAM-1, and uncover novel roles for p53 and DRAM-1 beyond cell death and autophagy regulation. Still, these pathways necessitate further investigation and harness a great potential to be targeted therapeutically to enhance tumour cell death.

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