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Title: Characterization of Wip1 Function in Tumourigenesis
Authors: XIA YUN
Keywords: phosphatase,Wip1,MAPK,apoptosis,p53,UV radiation
Issue Date: 8-Jul-2009
Citation: XIA YUN (2009-07-08). Characterization of Wip1 Function in Tumourigenesis. ScholarBank@NUS Repository.
Abstract: The Wild-type p53-induced phosphatase 1 (Wip1) is an oncogenic protein, which belongs to the protein phosphatase type 2C family. Wip1 plays important roles in regulating DNA damage-induced cell cycle checkpoints. The involvement of Wip1 in DNA damage pathway confers its oncogenic properities. However, it is still obscure if Wip1 has any function in regulating other facets of tumourigenesis such as apoptosis. Therefore, one important aim of this study is to investigate the roles of Wip1 in regulating apoptosis. We immortalized the mouse embryonic fibroblasts derived from wild-type and Wip1-/- mice with SV40 large T antigen. The elimination of Wip1 causes higher apoptotic responses upon DNA damage, oxidative stress and ribotoxic stress. In Wip1-/- MEFs, we observed higher activities of both p38-ATF2 and JNK-c-Jun signaling. In agreement with the higher activity of JNK-c-Jun signaling in stress-stimulated Wip1-/- MEFs, FasL transcription is also induced more significantly than that in wild-type MEFs, contributing to higher susceptibility to apoptosis. Not only normal cells but also cancer cells are sensitized to stress-induced apoptosis in the absence of Wip1. Inhibition of both p38 and JNK signaling successfully rescues stress-induced apoptosis in Wip1-/- MEFs. Moreover, the phosphorylation and activation of MKK4, but not MKK7 is differentially regulated between wild-type and Wip1-/- MEFs. In vitro phosphatase assay further indicated that Wip1 preferentially dephosphorylates Thr261 residue, but not Ser257 residue of MKK4. Thus, Wip1 plays multiple roles in regulating apoptosis in response to a variety of environmental stresses. The second part of my study was to investigate how Wip1 is regulated in response to UV-induced DNA damage. In MCF-7 cells, Wip1 protein level is induced upon low doses of UV radiation accompanied with cell cycle checkpoints. However, Wip1 protein level is suppressed upon high doses of UV radiation in parallel with apoptosis. Moreover, the high-dose UV-mediated decrease of Wip1 protein is not a consequence of apoptosis. In response to low doses of UV radiation, Wip1 protein is transcriptionally induced in a p53-dependent manner. In response to high doses of UV radiation, Wip1 protein level is suppressed by both transcriptional and post-translational machineries in a p53-independent manner. Our current results suggest that Wip1 protein is regulated by the proteasome-mediated degradation. However, further experiments need to be done in order to understand whether Wip1 is directly degraded through the ubituiqin-proeasome-mediated pathway. We speculate that the protein level of Wip1 might act as a mediator of the cell fate in response to UV radiation. Higher protein level of Wip1 upon UV radiation may lead to cell cycle checkpoints, while lower protein level of Wip1 is possibly related to apoptosis. It is not known yet what determines the fate of Wip1 protein upon different doses of UV radiation. These results indicate complex regulatory mechanisms of Wip1 protein in DNA damage signaling. Further studies are required to promote our understanding of the Wip1 function in tumourigenesis.
Appears in Collections:Ph.D Theses (Open)

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