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|Title:||CELLULAR MECHANISMS INVOLVED IN AGEING AND AGE-RELATED DISEASES||Authors:||HONG SHIN YEE||Keywords:||Ageing, TXNIP, Metabolism, ER stress, Cancer||Issue Date:||21-Aug-2015||Citation:||HONG SHIN YEE (2015-08-21). CELLULAR MECHANISMS INVOLVED IN AGEING AND AGE-RELATED DISEASES. ScholarBank@NUS Repository.||Abstract:||In this project, I addressed a number of important questions related to ageing and the major age-associated disease cancer. I investigated the potential role of mitochondrial protein acylation in ageing associated mitochondrial dysfunction. I found that mitochondrial protein acylation, specifically succinylation, increases with age in C. elegans and D. melanogaster (but not in rodents). This suggests that protein acylation may contribute to ageing associated mitochondrial dysfunction in these organisms. In relation to cancer, I studied the regulation of thioredoxin interacting protein (TXNIP). TXNIP is known to inhibit cellular glucose metabolism. I showed that growth factor signalling inhibits TXNIP expression, which may explain at least in part the observation that TXNIP is frequently downregulated in cancer. My data also suggest that downregulation of TXNIP in cancers with constitutive growth factor signaling may contribute to the Warburg effect by increasing cellular glucose uptake. Furthermore, 2-deoxyglucose, which has been used in clinical cancer trials, upregulated TXNIP expression via O-GlcNAcylation. This suggests a potential strategy to therapeutically induce TXNIP expression in cancer cells. Finally, I studied the mechanism of proteasome inhibitor treatment resistance in multiple myeloma. I found evidence for a role of mutation in the endoplasmic stress response factor XBP1 in mediating proteasome inhibitor resistance. In conclusion, my results suggest that deregulation of mitochondrial protein acylation, cellular glucose metabolism and the cellular ER stress response contribute to ageing and ageing-associated diseases.||URI:||http://scholarbank.nus.edu.sg/handle/10635/121915|
|Appears in Collections:||Ph.D Theses (Open)|
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