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The Role of Glycogen Synthase Kinase-3β in Normal Haematopoiesis, Angiogenesis and Leukaemia

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Abstract:

Glycogen synthase kinase 3 beta (GSK-3β) was one of the first kinases identified and studied, initially for its role in the regulation of glycogen synthesis. Over the past decade, interest in GSK-3β has grown far beyond glycogen metabolism, and this is due in large measure to the critical role that GSK-3β plays in the regulation of many other cellular processes, particularly cell proliferation and apoptosis. GSK-3β has been shown to regulate the proteolysis and sub-cellular compartmentalization of a number of proteins directly involved in the regulation of cell cycling, proliferation, differentiation and apoptosis. GSK-3β also regulates the degradation of proteins that regulate gene expression and thus affects a variety of important cell functions. Specifically, GSK-3β controls the degradation of β- catenin, the main effector of Wnt that regulates haematopoiesis and stem cell function. In this case GSK-3β is a negative regulator of Wnt. In contrast, GSK-3β positively regulates NF-κB, another important biochemical pathway also involved in the regulation of multiple aspects of normal and aberrant haematopoiesis. GSK-3β regulates degradation of IκB, a central inhibitor of NF-κB. In this way, GSK-3β acts to control the resistance of leukaemic cells to chemotherapy through the modulation of NF-κB, a critical factor in maintaining leukaemic cell growth. In addition, GSK-3β regulates the pro-inflammatory activity of NF-κB. As GSK-3β is a pleiotropic regulator, inhibitors may increase the range of novel anti-leukaemic and anti-inflammatory drugs that control immune response.

Keywords: GSK-3β inhibition; Haematopoiesis; NF-κB; Wnt; angiogenesis; haematopoietic stem cell; leukaemogenesis; β-catenin

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986708784638834

Affiliations: Sydney Cord & Marrow Transplant Facility, Sydney Children's Hospital, Australia.

Publication date: June 1, 2008

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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