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Raimo Tuominen and Johann Hofmann

Session 4: SER/THR KINASES II

Chair: Prof. Johann Hofmann, Innsbruck Medical University
 

Project coordinator Raimo Tuominen
and Prof. Johann Hofmann
Lectures and Oral Communications in Red are from members of our Consortium.
 
 


Protein Kinases as Drug Targets for The Treatment of Chronic Inflammatory Diseases
Prof. Sir Philip Cohen, University of Dundee, UK
 

    Protein Kinase CK2 as a “Drugable” Target
Prof. Lorenzo Pinna, Venetian Institute for Molecular Medicine, Italy
 
    Neuroprotection Related to Cyclins and CDKs in Acute Neuronal Excitotoxicity of Stroke And Epilepsy
Dr. Serge Timsit, Neurokin S.A.R.L., France


 


Protein Kinases as Drug Targets for The Treatment of Chronic Inflammatory Diseases
Prof. Sir Philip Cohen, University of Dundee, UK

 

Infection by pathogens stimulates macrophages to produce pro-inflammatory cytokines and inflammatory mediators, which are released in the circulation to mount the innate immune responses that fight the invading pathogen. However, this defence mechanism is a double-edged sword because the uncontrolled production of pro-inflammatory cytokines, like tumour necrosis factor (TNF), can cause chronic inflammatory diseases, such as rheumatoid arthritis. For this reason, the development of orally active drugs that suppress the production of TNF and other pro-inflammatory cytokines is of major interest to the pharmaceutical industry.

In this talk I will give an overview of the protein kinase cascades that control the production of pro-inflammatory cytokines in response to bacterial infection, with emphasis on recent findings from my laboratory. These studies suggest that, despite its current popularity as a drug target, p38
a MAP Kinase may not be the most appropriate protein kinase to target for an anti-inflammatory drug, due to the key role it plays in the feedback regulation of these signalling pathways.
 

 

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Protein Kinase CK2 as a “Drugable” Target
Prof. Lorenzo A. Pinna
Venetian Institute for Molecula Medicine (VIMM) and
Department of Biological Chemistry, The University of Padova, Padova, Italy



The acronym CK2 denotes a pleiotropic Ser/Thr protein kinase whose continuously growing list of substrates includes >300 proteins implicated in a wide variety of cell functions with special reference to signal transduction, gene expression, DNA repair and protein synthesis. Unlike the majority of protein kinases which are turned on only in response to specific stimuli, the catalytic subunits of CK2 (
aand/or a) are constitutively active either alone or in combination with the regulatory b-subunits to give a heterotetrameric holoenzyme ubiquitous in eukaryotes. Elevated CK2 activity is suspected to underlie a number of pathological situations, notably neoplasia: CK2 is abnormally high in tumours, and transfection of CK2 catalytic subunits contributes to the enhancement of the tumour phenotype in several experimental models. The rising concept is that CK2 plays a global role as an anti-apoptotic agent and by doing that it may promote cell survival even in circumstances where programmed cell death would be desirable. The recent development of specific, cell permeable CK2 inhibitors has provided a valuable tool to validate the implication of CK2 in the survival of tumour cells and in perspective to cure those kinds of cancer whose key feature is deregulation of apoptosis. The selectivity of these compounds relies on the size and shape of a hydrophobic pocket, which in CK2 is smaller than in the majority of other protein kinases, as revealed by structural and mutational analyses. The in vitro efficacy of CK2 inhibitors correlates with their cytotoxic effect on cells derived from a wide specrum of tumours, including prostate carcinomas, leukemias, lymphomas and multiple myelomas.

 

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Neuroprotection Related to Cyclins and CDKs in Acute Neuronal Excitotoxicity of Stroke And Epilepsy
Dr. Serge Timsit
NEUROKIN, INSERM U-29, INMED, Parc Scientifique de Luminy, 13273 Marseille cedex 09, France
 

Excitotoxicity, the accumulation of glutamate and the excessive activation of glutamate receptors, plays a central role in neuronal death associated with neurological disorders such as stroke and status epilepticus. The effect of excitatory amino acids is transduced primarily through ionotropic receptors of NMDA, AMPA and kainate subtypes. Data suggest that damage produced by local injections of amino acids are of dual type: a rapid classical necrosis type of neuronal death associated with swelling and a slower apoptotic type of neuronal death associated with programmed cell death.

Programmed cell death may result, in part, from aberrant control of the cell cycle. Cyclins, and among them Cyclin D1, are important proteins in the cell cycle. Cyclin D1 associates primarily with Cyclin-Dependent Kinases CDK4, 6. After four vessels occlusion or following seizures induced by kainate, cyclin D1 mRNA and protein are induced respectively in CA1 and CA3 dying neurons known to be particularly vulnerable to these procedures (Timsit et al., 1999). The complex Cyclin D1/CDK4 has been shown to be instrumental in excitotoxicity. However other CDKs, not involved in the cell cycle, have also been involved in neuronal death.

We analyzed the neuroprotective potential of selective pharmacological CDK inhibitors using both in vitro and in vivo paradigms of excitotoxicity/ischemia. Evaluation of the neuroprotective effect of a panel of CDK inhibitors using in vitro models of neuronal excitotoxicity allowed the identification of NK-102 as a promising candidate. Electrophysiological analysis of treated neurons revealed that it protected also the functionality of neuronal synapses. In a mouse model of permanent occlusion of the middle cerebral artery, NK-102 protected the apoptotic penumbra-like area of the lesion but not the necrotic-core.

Altogether, our results showed the potential role of CDK inhibitors as potential therapy in stroke.

 

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