p53 functions as an important tumour suppressor through its ability to regulate a number of important cellular processes such as cell cycle arrest, apoptosis, DNA repair, senescence, and angiogenesis. An in vivo genetic modifier screen performed using Drosophila melanogaster resulted in the identification of D. melanogaster brain tumour (brat) as a putative modifier of of the p53 small eye phenotype. Mammalian homologs of brat are members of the tripartite motif family that contain a c-terminal NHL domain. We focus on elucidating the in vivo role of one such homolog, BERP, through the generation and characterization of a classical gene-deletion mouse mutant. We report that BERP-deficient mice exhibit enhanced learning/memory, increased fear, impaired motor coordination, and increased resistance to PTZ -induced seizures. Electrophysiological and biochemical studies show a decrease in mIPSC amplitude along with a decrease in cell surface expression of gamma2 subunit-containing GABA A receptors in the brains of BERP-deficient mice. In addition, no effect of genotype is apparent when examining BERP mRNA levels in the brain. This suggests that the decreased cell surface expression of gamma2 subunit-containing GABA A receptors is likely a posttranscriptional phenomenon and supports the possibility that BERP may be involved in the intracellular trafficking of GABA A receptors. In investigating the possible relationship between BERP and p53, we identify the presence of a transcriptionally competent p53 response element within the first intron of the human BERP genomic locus and demonstrate that the BERP expression is up regulated in a p53-dependent manner both in vitro and in vivo. These results support the interpretation that BERP is a novel p53-regulated gene and suggest a new role for p53 in the regulation of GABA A receptor trafficking and epileptogenesis.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/32004 |
| Date | 17 January 2012 |
| Creators | Cheung, Carol Chui-San |
| Contributors | Mak, Tak Wah |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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