Glucose—a sweet way to die: Metabolic switching modulates tumor cell death

TRAIL, a putative anticancer cytokine, induces extrinsic cell death by activating the caspase cascade directly (Type I cells) via the death-inducing signaling complex (DISC) or indirectly (Type II cells) by caspase-8 cleavage of Bid and activation of the mitochondrial cell death pathway. Cancer cells are characterized by their dependence on aerobic glycolysis, which, although inefficient in terms of ATP production, facilitates tumor metabolism. Our studies show that TRAIL-induced cell death is significantly affected by the metabolic status of the cell. Inhibiting glycolysis with 2-deoxyglucose potentiates TRAIL-induced cell death, whereas glucose deprivation can paradoxically inhibit apoptosis. These conflicting responses to glycolysis inhibition are modulated by the balance between the Akt and AMPK pathways and their subsequent downstream regulation of mTORC1. This results in marked changes in protein translation, in which the equilibrium between anti- and pro-apoptotic Bcl-2 family member proteins is decided by their individual degradation rates. This regulates the mitochondrial cell death pathway and alters its sensitivity not only to TRAIL, but to ABT-737, a Bcl-2 inhibitor. Taken together, our studies show that the sensitivity of cancer cells to apoptosis can be modulated by targeting their unique metabolism in order to enhance sensitivity to apoptotic agents.     

Heterokaryon incompatibility in fungi—more than just another way to die

In filamentous fungi heterokaryon (vegetative) compatibility is regulated by a number of different loci. Vegetative incompatibility is most often detected as the inability to form a prototrophic heterokaryon under forcing conditions, or as the formation of a barrage when two incompatible strains interact. Vegetative compatibility has been used as a multilocus phenotype in analysis of fungal populations. In some highly clonal populations the vegetative-compatibility phenotype is correlated with pathogenicity. The molecular basis for vegetative compatibility is not well understood. Fourhet loci have been cloned fromNeurospora crasset orPodospora anserina, inch but no two are alike and it is clear that thehet genes themselves do not encode the gene products that are directly responsible for cell death. We suggest that a broader view of vegetative compatibility would include genes that are responsible for prefusion, fusion, and postfusion activities. Postfusion activities could include the fungal apoptotic apparatus since microscopic observations of cell death resemble those in higher plants and animals.     

Intra-Golgi transport: a way to a new paradigm?

The morpho-functional principles of intra-Golgi transport are, surprisingly, still not clear, which is in marked contrast to our advanced knowledge of the underlying molecular machineries. Recently, the conceptual and technological hindrances that had delayed progress in this area have been disappearing, and a cluster of powerful morphological techniques has been revealing new glimpses of the organization of traffic in intact cells. Here, we discuss the new concepts around the present models of intra-Golgi transport.     

LKB1: a sweet side to Peutz-Jeghers syndrome?

The recent discovery that the tumour suppressor LKB1 is an upstream kinase in the AMP-activated protein kinase (AMPK) cascade provided a molecular link between energy metabolism and cancer. A recent study by Shaw and colleagues elucidated the role of LKB1 in type 2 diabetes. Deletion of the gene encoding LKB1 in the liver leads to marked hyperglycaemia as a consequence of increased gluconeogenic gene expression and hepatic glucose output. Importantly, the absence of LKB1 in the liver abolishes the effect of lowering glucose level caused by metformin, a drug that is widely used for the treatment of type 2 diabetes. These findings should help solve the mystery surrounding the function of metformin, which has lasted for >30 years.     

Protein disulfide isomerases – a way to tackle malaria

Protein disulfide isomerases (PDIs) ensure that specific substrate proteins are correctly folded. PDI activity plays an essential role in malaria transmission. Here we provide an overview of the role of PDIs in malaria-causing Plasmodium parasites and outline why PDI inhibition could be a novel way to treat malaria and prevent transmission.     

Neurostimulation: a new way to influence cortical excitability?

Recent work in humans suggests that strong static magnets can modulate cortical excitability for a limited period of time. Can this provide an alternative to current neurostimulation approaches?     

Protein signatures—A novel way to classify proteins

A method is developed to classify proteins by establishing their familial identity based on the presence and the absence of characteristic signature dipeptides. It is hoped that this method will lead to the establishment of a theoretical basis for the determination of interrelationships among proteins.     

Glucose response to bursting-spiking pancreatic β-cells by a barrier kinetic model

A mathematical model of the pancreatic -cell electrical activity was developed using a barrier kinetic model. Our model incorpolates the glucose sensitive channel which is known to conduct K⁺ in the absence of glucose. The model also incorporates Ca _i sensitive K⁺ channels which are inhibited by intracellular H⁺ ions. It is described by three non-linear simultaneous differential equations. Numerical integration of these equations allowed us to examine the effect of glucose and of external Ca²⁺ ions on the electrical and cellular activity of the -cell. Our results show that the contribution of glucose-sensitive channel activity, if not completely inhibited, plays a very important role in determining the bursting periodicity. Our results also shows that even a small decrease in pH _i is sufficient to change a bursting -cell to a spiking one. The voltage dependence of calcium sensitive K⁺ channels, however, affects little to the bursting mode of the electrical activity. Our simulation supports an incomplete selectivity of the voltage dependent calcium channel for calcium ions with low external [Ca²⁺]. It also supports the role of [Ca] _i as an inhibitor of this channel when [Ca] _i becomes unusually high.This work was supported by NSF PCM 82 15583     

Is there more than one way to attract a pollen tube?

ZmEA1 (Zea mays egg apparatus 1) is expressed only in the egg and synergid cells. Embryo sacs with presumed reduced expression of ZmEA1 fail to attract pollen tubes. Together with data from Arabidopsis mutants and from elegant laser ablation experiments in Torenia fournieri, these results indicate that embryo sacs send signals to the incoming pollen tubes. We need to decipher how such signals are perceived and determine if the signals are species-specific.     

Dermacentor reticulatus – a tick on its way from glacial refugia to a panmictic Eurasian population

The ornate dog tick (Dermacentor reticulatus) shows a recently expanding geographic distribution. Knowledge on its intraspecific variability, population structure, rate of genetic diversity and divergence, including its evolution and geographic distribution, is crucial to understand its dispersal capacity. All such information would help to evaluate the potential risk of future spread of associated pathogens of medical and veterinary concern. A set of 865 D. reticulatus ticks was collected from 65 localities across 21 countries, from Portugal in the west to Kazakhstan and southern Russia in the east. Cluster analyses of 16 microsatellite loci were combined with nuclear (ITS2, 18S) and mitochondrial (12S, 16S, COI) sequence data to uncover the ticks’ population structures and geographical patterns. Approximate Bayesian computation was applied to model evolutionary relationships among the found clusters. Low variability and a weak phylogenetic signal showing an east–west cline were detected both for mitochondrial and nuclear sequence markers. Microsatellite analyses revealed three genetic clusters, where the eastern and western cluster gradient was supplemented by a third, northern cluster. Alternative scenarios could explain such a tripartite population structure by independent formation of clusters in separate refugia, limited gene flow connected with isolation by distance causing a “bipolar pattern”, and the northern cluster deriving from admixture between the eastern and western populations. The best supported demographic scenario of this tick species indicates that the northern cluster derived from admixture between the eastern and western populations 441 (median) to 224 (mode) generations ago, suggesting a possible link with the end of the Little Ice Age in Europe.     

GM crops in Ethiopia: a realistic way to increase agricultural performance?

Much has been published on the application of genetically modified (GM) crops in Africa, but agricultural performance has hardly been addressed. This paper discusses the main consequences of GM crops on agricultural performance in Ethiopia. Three main criteria of performance - productivity, equitability and sustainability - are evaluated in the context of the Ethiopian agricultural sector. We conclude that the application of GM crops can improve the agricultural productivity and sustainability, whereas equitability cannot be stimulated and might even exacerbate the gap between socioeconomic classes. Before introducing GM crops to Ethiopian agriculture, regulatory issues should be addressed, public research should be fostered, and more ex ante values and socioeconomic studies should be included.