| |||
|
|
|||
|
      |
|
 |
|
| |||||||||||
| |||||||||||
| |||||||||||
| | | | ||||||||
|
In brief: January 2008Circadian rhythms Rev-erb The mechanism by which the circadian clock is integrated into metabolic systems is poorly understood. Yin et al. show that the haem prosthetic group binds to the orphan nuclear receptor Rev-erb T-cell development Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. During T-cell development, the intensity of signals that thymocytes receive through the T-cell receptor (TCR) determines their fate — weak signals allow positive selection whereas strong signals cause negative selection. Here, Gallo et al. show that calcineurin signalling enables such signal discrimination. In wild-type mice, two subpopulations of CD69- double-positive thymocytes were shown to exist: one with high levels of phosphorylated ERK (extracellular-signal-regulated kinase) and the other with low levels. However, in mice that lack calcineurin (or the downstream transcription factors NFATc2 and NFATc3), the subpopulation with high ERK phosphorylation was absent and positive selection was impaired. Early calcineurin signalling (probably through the pre-TCR) was shown to sensitize the RAF–MEK–ERK pathway to increase the dynamic range (or bandwidth) of subsequent TCR signals, thereby enabling thymocytes to respond to weak signals that would otherwise not be detected. Targeted therapeutics An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic The anticancer drug imatinib exerts its effect in gastrointestinal stromal tumours (GISTs) by targeting the KIT kinase. However, it also causes cardiotoxicity through its effect on ABL kinase. Fernández et al. have modified imatinib so that it targets JUN N-terminal kinase — a change required for prevention of cardiotoxicity — and KIT but not ABL. In a GIST mouse model the new compound, named WBZ_4, had therapeutic effect, with reduced cardiotoxicity. CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice This paper shows that the low-molecular-weight compound CP-31398, which restores the tumour-suppressor functions of mutant p53 in tumour cells in vitro, is also effective in vivo. CP-31398 blocked UVB-induced skin carcinogenesis — known to induce p53 mutations — in mouse models. Treatment with CP-31398 induced expression of p53-dependent genes and induced mitochondrial translocation of p53. These events were followed by apoptosis in UVB-irradiated wild-type mice but not their p53-deficient litter mates. Genomics Transposase-derived transcription factors regulate light signaling in Arabidopsis. These authors show that FHY3 and FAR1, both related to Mutator-like transposases, modulate signalling through the photoreceptor phytochrome A. By directly binding to the promoters of FHY1 and FHL, the transposases activate transcription to ensure correct responses to far-red light. Phylogenetic and functional analyses imply that one or more MULE transposase genes gave rise to FHY3- and FAR1-related genes during angiosperm evolution, which allowed them to adapt to changing light conditions. The results also confirm that transposable elements can be a source of new transcription factors during evolution. Axon growth Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals The authors found that toll-like receptor 3 (TLR3) is expressed in neurons and is concentrated in growth cones. Activation of TLR3 with poly I:C rapidly induced growth cone collapse and inhibited neuronal outgrowth. These effects were independent of NF- Glucose homeostasis Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways Glucose homeostasis is in part regulated by central brain pathways, suggesting that these could be targeted to treat type 2 diabetes. Here the authors showed that serotonin 2C receptor agonists can improve glucose homeostasis in mouse models of obesity and in patients with type 2 diabetes, and that these effects are mediated by a pathway that involves the activation of melanocortin 4 receptors in the hypothalamus. G-protein-coupled receptors Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. To help elucidate the function of the many G-protein-coupled receptors (GPCRs) whose role is not understood, Regard and colleagues developed a pertussis toxin-based genetic method that achieved tissue-specific inhibition of Gi-mediated signalling pathways in vivo. Using this model the authors showed that 3-iodothyronamine, a thyroid hormone metabolite, and the protease-activated receptor 2 could regulate insulin secretion and may contribute to physiological regulation of glucose metabolism. Imaging and visualization Single-molecule tracking by fours The need to track single fluorescently labeled proteins in living cells has created a desire for three-dimensional single-particle tracking methods using low-level illumination. Lessard et al. show that they can track single quantum dots using only 10 µW of energy by using four optical fibers coupled to individual detectors to effectively create four confocal pinholes that provide location information for feedback control–based tracking. | |
| ||||||||
| |||||||||||
 | |||||||||||
| |||||||||||
| |||||||||||
| |||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||
| |||||||||||
, a heme sensor that coordinates metabolic and circadian pathways.
B, which mediates many of the downstream signalling effects of TRL3 activation. Poly I:C injections resulted in impaired axonal development and sensorimotor deficits in wild-type but not in TRL-/- mouse pups. The findings indicate that TLR3 activation negatively regulates axonal growth and might provide a target for injury-repair strategies.