Characterisation of DRAM-1 in vitro and in vivo

Mah, Li Yen (2012) Characterisation of DRAM-1 in vitro and in vivo. PhD thesis, University of Glasgow.

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.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from Cancer Research UK.
• Keywords: DRAM-1, autophagy, in vivo, in vitro
• Subjects: Q Science > QH Natural history > QH301 Biology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Ryan, Prof. Kevin
• Date of Award: 2012
• Depositing User: Dr. Li Yen Mah
• Unique ID: glathesis:2012-3751
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 26 Nov 2012
• Last Modified: 16 Nov 2015 10:04
• URI: https://theses.gla.ac.uk/id/eprint/3751