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Diabetes mellitus is associated with moderate cognitive deficits and neurophysiological and structural changes in the brain, a condition that may be referred to as diabetic encephalopathy. Diabetes increases the risk of dementia, particularly in the elderly. The emerging view is that the diabetic brain features many symptoms that are best described as(More)
FoxO (forkhead box O; forkhead members of the O class) are transcription factors that function under the control of insulin/insulin-like signalling. FoxO factors have been associated with a multitude of biological processes, including cell-cycle, cell death, DNA repair, metabolism and protection from oxidative stress. Central to the regulation of FoxO(More)
Forkhead transcription factors of the FoxO-group are associated with cellular processes like cell cycle progression and DNA-repair. FoxO function is regulated by protein kinase B (PKB) via the phosphatidylinositol 3-kinase/PKB survival pathway. Phosphorylation of serine and threonine residues in specific PKB phosphorylation motifs leads to exclusion of(More)
Insulin and its receptor are both present in the central nervous system and are implicated in neuronal survival and hippocampal synaptic plasticity. Here we show that insulin activates phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB), and results in an induction of long-term depression (LTD) in hippocampal CA1 neurones. Evaluation of the(More)
Insulin is best known for its role in peripheral glucose homeostasis. Less studied, but not less important, is its role in the central nervous system. Insulin and its receptor are located in the central nervous system and are both implicated in neuronal survival and synaptic plasticity. Interestingly, over the past few years it has become evident that the(More)
The versatile cytokine transforming growth factor β (TGF-β) regulates cellular growth, differentiation, and migration during embryonic development and adult tissue homeostasis. Activation of TGF-β receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and(More)
Forkhead box, class O (FoxO) transcription factors are inhibited by insulin-induced FoxO phosphorylation. Recently, acetylation of FoxO factors by calcium response element-binding (CREB)-binding protein (CBP) and/or p300 has been identified as a novel regulatory pathway, although the exact consequences of acetylation remain unclear. We propose that binding(More)
Transforming growth factor-β (TGFβ) binding to its receptor leads to intracellular phosphorylation of Smad2 and Smad3, which oligomerize with Smad4. These complexes accumulate in the nucleus and induce gene transcription. Here we describe mitogen- and stress-activated kinase 1 (MSK1) as an antagonist of TGFβ-induced cell death. Induction of MSK1 activity by(More)
Forkhead members of the 'O' class (FoxO) are transcription factors crucial for the regulation of metabolism, cell cycle, cell death and cell survival. FoxO factors are regulated by insulin-mediated activation of PI3K (phosphoinositide 3-kinase)-PKB (protein kinase B) signalling. Activation of PI3K-PKB signalling results in the phosphorylation of FoxO(More)
Continuous, nonrandom cell death during development of the dopaminergic system is carefully orchestrated by locally secreted growth factors and the expression of transcription factors to ensure every neuron is carefully placed in its appropriate position and no 'miswiring' occurs. We hypothesize that the machinery directly responsible for executing cell(More)