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Title: Characterization of the role of Fat10 in Tumorigenesis
Keywords: FAT10 MAD2 aneuploidy Cancer TNF-alpha NF-kB
Issue Date: 17-Aug-2009
Citation: REN JIANWEI (2009-08-17). Characterization of the role of Fat10 in Tumorigenesis. ScholarBank@NUS Repository.
Abstract: Aneuploidy is a key process in tumorigenesis. Dysfunction of the mitotic spindle checkpoint proteins has been implicated as a cause of aneuploidy in cells.In this thesis, we discovered that FAT10, an ubiquitin-like modifier that is able to interact with spindle checkpoint protein MAD2, is upregulated in the tumors of 90% of HCC patients. Moreover, FAT10 expression was found to be highly upregulated in other cancers of the gastrointestinal tract and female reproductive system.In characterizing functions of FAT10, we have found that FAT10 interacted with MAD2 during mitosis. Notably, we showed that localization of MAD2 at the kinetochore during the prometaphase stage of the cell cycle was greatly reduced in FAT10-overexpressing cells. Furthermore, compared with parental HCT116 cells, FAT10-overexpressing cells have an abbreviated mitosis stage. Additionally, more nocodazole-treated FAT10-overexpressing cells escape mitotic controls and are multinucleate compared with parental cells. Significantly, we observed a higher degree of variability in chromosome number in cells overexpressing FAT10. Hence, our data suggest that high levels of FAT10 protein in cells lead to increased mitotic nondisjunction and chromosome instability.To investigate pathological significance of overexpression of FAT10 in tumors, I characterized the regulation of FAT10 gene expression and found that endogenous FAT10 expression was induced by inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) through activated NF-kB pathway. Interestingly, we observed that long term TNF-alpha/ IFN-gamma treatment could induce similar aberrance of numerical chromosomal stability that occurred in FAT10 overexpressing cells. My study has suggested that FAT10 may play roles in the development of TNF-alpha mediated chronic inflammation-associated tumorigenesis by inducing chromosomal instability.
Appears in Collections:Ph.D Theses (Open)

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