Cdk5 interacts with Hif-1α in neurons: A new hypoxic signalling mechanism?

Antoniou, Xanthi; Gassmann, Max; Ogunshola, Omolara O.

doi:10.1016/j.brainres.2010.10.071

Cited by 21 publications

(15 citation statements)

References 32 publications

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“…Recent observations suggest that apoptosis of neurons after brain ischemia is strongly associated with Cdk5 hyper-activation mediated by its activator p25 [9], however, normal signaling through the Cdk5/p35 complex promotes neuronal survival, whilst inhibition of normal Cdk5 activity may inhibit Hif-1α accumulation and concomitantly induce neuronal cell death [26]. Firstly, we optimized an in vitro model of low oxygen tension mimicking hypoxia during stroke, wherein hBMEC were exposed to 24h of low oxygen levels (1%).…”

Section: Resultsmentioning

confidence: 99%

Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia

Bosutti

Pennucci

et al. 2013

PLoS ONE

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Cyclin-dependent kinase-5 (Cdk5) is over-expressed in both neurons and microvessels in hypoxic regions of stroke tissue and has a significant pathological role following hyper-phosphorylation leading to calpain-induced cell death. Here, we have identified a critical role of Cdk5 in cytoskeleton/focal dynamics, wherein its activator, p35, redistributes along actin microfilaments of spreading cells co-localising with p(Tyr15)Cdk5, talin/integrin beta-1 at the lamellipodia in polarising cells. Cdk5 inhibition (roscovitine) resulted in actin-cytoskeleton disorganisation, prevention of protein co-localization and inhibition of movement. Cells expressing Cdk5 (D144N) kinase mutant, were unable to spread, migrate and form tube-like structures or sprouts, while Cdk5 wild-type over-expression showed enhanced motility and angiogenesis in vitro, which was maintained during hypoxia. Gene microarray studies demonstrated myocyte enhancer factor (MEF2C) as a substrate for Cdk5-mediated angiogenesis in vitro. MEF2C showed nuclear co-immunoprecipitation with Cdk5 and almost complete inhibition of differentiation and sprout formation following siRNA knock-down. In hypoxia, insertion of Cdk5/p25-inhibitory peptide (CIP) vector preserved and enhanced in vitro angiogenesis. These results demonstrate the existence of critical and complementary signalling pathways through Cdk5 and p35, and through which coordination is a required factor for successful angiogenesis in sustained hypoxic condition.

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Section: Resultsmentioning

confidence: 99%

Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia

Bosutti

Pennucci

et al. 2013

PLoS ONE

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“…This p25 is capable of activating cdk5. An association of p25 with Cdk5 could form a stable complex, p25/Cdk5, which induces various pathological events that are Aβ formation, tau hyperphosphorylation, synaptic plasticity, neuronal cell apoptosis, reactivation of cell cycle and oxidative stress and mitochondrial dysfunction, eventually leading to neurons death oxygen deprivation, which acts as a new hypoxiamediated signaling pathway [32]. Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, which is a key receptor that mediates dopamine-associated brain functions such as mood, reward, and emotion [33].…”

Section: Cdk5 Is Essential For Neuronal Survivalmentioning

confidence: 99%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

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“…Ins-1 cells cultured in 1 mmol/L sphinganine, 1-deoxysphinganine, or BSA for 24 h were lysed as previously described (15). Aliquots corresponding to 35 mg of proteins were separated by SDS-PAGE electrophoresis, blotted, and probed overnight at 4°C.…”

Section: Western Blottingmentioning

confidence: 99%

Deoxysphingolipids, Novel Biomarkers for Type 2 Diabetes, Are Cytotoxic for Insulin-Producing Cells

et al. 2014

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Irreversible failure of pancreatic β-cells is the main culprit in the pathophysiology of diabetes, a disease that is now a global epidemic. Recently, elevated plasma levels of deoxysphingolipids, including 1-deoxysphinganine, have been identified as a novel biomarker for the disease. In this study, we analyzed whether deoxysphingolipids directly compromise the functionality of insulin-producing Ins-1 cells and primary islets. Treatment with 1-deoxysphinganine induced dose-dependent cytotoxicity with senescent, necrotic, and apoptotic characteristics and compromised glucose-stimulated insulin secretion. In addition, 1-deoxysphinganine altered cytoskeleton dynamics, resulting in intracellular accumulation of filamentous actin and activation of the Rho family GTPase Rac1. Moreover, 1-deoxysphinganine selectively upregulated ceramide synthase 5 expression and was converted to 1-deoxy-dihydroceramides without altering normal ceramide levels. Inhibition of intracellular 1-deoxysphinganine trafficking and ceramide synthesis improved the viability of the cells, indicating that the intracellular metabolites of 1-deoxysphinganine contribute to its cytotoxicity. Analyses of signaling pathways identified Jun N-terminal kinase and p38 mitogen-activated protein kinase as antagonistic effectors of cellular senescence. The results revealed that 1-deoxysphinganine is a cytotoxic lipid for insulin-producing cells, suggesting that the increased levels of this sphingolipid observed in diabetic patients may contribute to the reduced functionality of pancreatic β-cells. Thus, targeting deoxysphingolipid synthesis may complement the currently available therapies for diabetes.

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Cdk5 interacts with Hif-1α in neurons: A new hypoxic signalling mechanism?

Cited by 21 publications

References 32 publications

Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia

Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia

The Role of Cdk5 in Alzheimer’s Disease

Deoxysphingolipids, Novel Biomarkers for Type 2 Diabetes, Are Cytotoxic for Insulin-Producing Cells

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