Posted by Josh on October 30, 2001 at 00:28:40:
Ellen, here is the abstract for the article from Cellular & Molecular Biology Letters...
HOW TO CURE DIABETES WITHOUT CAUSING CANCER
PHILIP COHEN
University of Dundee, Department of Biochemistry, Dundee DD1 4HN,
Scotland
The abnormal phosphorylation of proteins is a cause or consequence of major
diseases such as arthritis, cancer and diabetes, raising the question of whether
drugs that modulate the activities of kinases and phosphatases might be
efficacious for the treatment of these and other conditions. Over the past few
years, many such compounds have been developed and several are showing
promise in human clinical trials [1]. In the first part of the talk, I will present an
overview of progress in this area, and in the second discuss recent progress in
generating inhibitors and understanding the regulation of glycogen synthase
kinase-3 (GSK3) a potential therapeutic target for the treatment of diabetes.
We identified GSK3 over 20 years ago and its acute inhibition by protein kinase
B (PKB) appears to contribute to the insulin-induced stimulation and glycogen
synthesis and protein synthesis in vivo. For this reason, drugs that inhibit GSK3
activity may mimic these effects of insulin and hence show efficacy for the
treatment of diabetes. Cell permeant compounds that inhibit GSK3 relatively
specifically have recently been developed, which trigger the dephosphorylation
and activation of glycogen synthase and the conversion of glucose to glycogen
in cell based assays. They also mimic the ability of insulin to suppress
transcription of phosphoenolpyruvate carboxykinase and glucose 6 phosphatase
[2], and may therefore prevent the production of glucose by the liver as well as
by increasing its rate of disposal in peripheral tissues. However, the inhibition
of GSK3 also plays a key role in the specification of cell fates during embryonic
development. This leads to the dephosphorylation and stabilisation of ü -catenin,
which then enters the nucleus and regulates the transcription of developmental
genes. Since mutated forms of ü -catenin that stabilise this protein are frequently
overexpressed in human tumours, there is a potential danger that long term
treatment with GSK3 inhibitors could promote cell transformation and cancer.
In the final part of the talk, I will present our recent work on the mechanisms by
which insulin and developmental signals control GSK3 activity. These studies
suggest novel ways of developing GSK3 inhibitors that may mimic the action of
insulin without having the potential to be oncogenic [3].
REFERENCES
1. Cohen P. The development and therapeutic potential of protein kinase
inhibitors. Curr. Opin. Chem. Biol. 3 (1999) 459-465.
2. Lochhead, P.A., Salt, I.P., Walker, K.S., Hardie, D.G. and Sutherland, C. 5-
aminoimidazole-4-carboxamide riboside mimics the effects of insulin on
the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-
phosphatase. Diabetes 49 (2000) 896-903.
3. Frame, S., Cohen, P. and Biondi, R.M. A common phosphate-binding site
explains the unique substrate specificity of GSK3 and its inactivation by
phosphorylation. Mol. Cell. 7 (2001) 1321-1327.