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  • br Conclusions In a former


    Conclusions In a former study we compared the modulating potential of halogenated 1H-benzimidazole derivatives towards CK2 catalytic subunits. Now we were interested if similar differences are also obtained using completely different substances. Some of these natural occurring compounds were already described as potent inhibitors of CK2 holoenzyme. As we already know CK2 does not only exists as tetramer in the serial dilution calculator but also in form of free catalytic and regulatory subunits. Therefore, it was interesting to examine if those inhibitors are also active against the free subunits CK2α and CK2α′. The study of Li et al. (2009) was the first one using 7 flavonoids as CK2 holoenzyme inhibitors. Afterwards several further research groups undertook more detailed experiments to estimate the inhibitory potential of this class of inhibitors and its derivatives (Golub et al., 2011, Lolli et al., 2012). Comparing the results from our present study with the results obtained by other research groups with the CK2 holoenzyme we can see a lower inhibitory effect towards the free catalytic subunits. Some of the new inhibitors, especially chrysoeriol as well as pedalatin, tricin and scutellarin are promising start points for further chemical optimization to obtain more efficient CK2 inhibitors.
    CK2 and hormonal regulation of carbohydrate metabolism Metabolism is a set of chemical reactions which allow organisms to grow and reproduce, maintain their structures and respond to the environment. It is usually divided into catabolism and anabolism. These chemical reactions are organized in metabolic pathways, which are catalyzed and regulated by a sequence of different enzymes. A great number of these enzymes are regulated by reversible phosphorylation reactions. The basic metabolic pathways and components are similar in various cell species [26] and regulation of these pathways is quite similar. Carbohydrates are the most abundant biological molecules. They function in energy storage, cellular signalling and are part of structural components. The carbohydrate metabolism and in particular glucose metabolism are mainly regulated by two hormones, insulin and glucagon. Low blood glucose triggers the release of glucagon from pancreatic α-cells, whereas, high blood glucose triggers the release of insulin from pancreatic β-cells. Transcription of the insulin gene in the β-cells of the pancreas is mainly regulated by the transcription factor Pdx1 also called IPF1, IDX1, STF1 and IUF [27]. It was recently shown that CK2 phosphorylated Pdx1 at threonine 231 and serine 232. Phosphorylation of Pdx1 by CK2 reduced the transcription factor activity of Pdx1 (Fig. 1), demonstrating that CK2 is implicated in the regulation of insulin production in pancreatic β-cells [28]. It was further shown that insulin treatment of β-cells resulted in an elevated CK2 kinase activity which down regulates insulin production. These results identified CK2 as a member of an autoregulatory pathway in pancreatic β-cells; regulating insulin production and release. This autoregulatory loop is shown in Fig. 1. Pharmacological inhibition of CK2 kinase activity with two different CK2 inhibitors resulted in an elevated insulin production and secretion. These results paved the way for CK2 to act as a target in diabetes therapy [29]. Pdx1 also regulates the transcription of the gene coding for synaptotagmin 1 which is a Ca sensor that plays a central role for insulin release in pancreatic β-cells [30]. It was shown that synaptotagmin 1 is phosphorylated by CK2 on one single site namely threonine 128. The function of the phosphorylation of synaptotagmin by CK2 awaits further examinations. Two possible functions may include binding to Ca ions and multimerization, both of which have been mapped to the vicinity of the CK2 phosphorylation site [31]. Insulin has been shown to increase CK2 activity in a number of cultured cells including 3T3-L1 and H4-IIE rat hepatoma cells [32], Balb/C3T3 fibroblasts and rat fat cells [33]. In contrast, Grande et al. [34] have reported a decrease in the activity of this kinase in the liver, whereas, Ahn and Krebs [35] found no change in CK2 activity in response to insulin. One reason for this discrepancy might be the kinetics of the insulin action on CK2 activity. It was shown by Sommercorn et al. [32] that CK2 is activated in 3T3-L1 cells 5min following exposure to insulin. Activation was maximal after 10min and persisted through 90min. Thus, time course experiments are absolutely necessary to determine the serial dilution calculator time point when insulin activates CK2. Interestingly, the protein level of the CK2 subunits was not altered after insulin treatment although the enzyme activity increased.