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Glycogen synthase kinase-3beta (GSK-3beta) has been demonstrated to play a critical role in a diverse range of cellular functions from cell fate determination to cancer development. It is also implicated to be involved in the pathogenesis of neurodegenerative diseases (e.g. Alzheimer's disease), cancers and endocrine disorders (e.g. Type II diabetes). To gain further insight into the cellular mechanisms mediated by GSK-3beta, proteomic approach to identify novel cellular targets has become popular in recent years. GSK-3beta was inhibited by treating with lithium and kenpaullone in SH-SY5Y cell model, and over-expressed in Chinese Hamster Ovary (CHO) Tet-Off cell model. To getting more reliable results, we have used both conventional 2-D approach and Difference Gel Electrophoresis (DIGE) approach for this proteomic study. In 2-D electrophoresis, samples were resolved by two-dimensional polyacrylamide gel-electrophoresis (2D-PAGE). Protein spots were excised from the gels for in-gel trypsin digestion and further subjected to protein identification using mass spectrometry (MALDI-TOF-MS or MS/MS). In the GSK-3beta inhibition approach, cofilin was found to be down-regulated and Pin1 was found to be up-regulated, these consequence events demonstrated inhibition of GSK-3beta would protect the cells from structure alteration and tau hyperphosphorylation. In the GSK-3beta activation approach, cyclin-dependent kinase 5 (CDK-5) was found to significantly up-regulated in tau and GSK-3beta/Tau over-expressed cells, confirmed by Western blotting and RT-PCR. This finding indicates there is a new pathway between GSK-3beta, tau and CDK-5. Pin1 is also identified to be up-regulated after GSK-3beta activation. This result indicated a protection mechanism in response to the accumulation of hyperphosphorylated tau proteins. Our study help to get a better understanding of the GSK-3beta mediated substrates and pathways that help us to identify novel targets for the treatment of neurodegenerative and other diseases mediated by GSK-3beta. / Mak, Ying Cheong. / "September 2007." / Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4588. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 157-181). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Thesis (Ph. D.)--University of Lund, 1998. / Originally issued as the author's doctoral thesis. Includes bibliographical references.

published_or_final_version / abstract / toc / Pharmacology / Master / Master of Philosophy

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