Phosphorylation by Akt within the ST loop of AMPK-α1 down-regulates its activation in tumour cells

The insulin/IGF-1 (insulin-like growth factor 1)-activated protein kinase Akt (also known as protein kinase B) phosphorylates Ser(487) in the ‘ST loop’ (serine/threonine-rich loop) within the C-terminal domain of AMPK-α1 (AMP-activated protein kinase-α1), leading to inhibition of phosphorylation by upstream kinases at the activating site, Thr(172). Surprisingly, the equivalent site on AMPK-α2, Ser(491), is not an Akt target and is modified instead by autophosphorylation. Stimulation of HEK (human embryonic kidney)-293 cells with IGF-1 caused reduced subsequent Thr(172) phosphorylation and activation of AMPK-α1 in response to the activator A769662 and the Ca(2+) ionophore A23187, effects we show to be dependent on Akt activation and Ser(487) phosphorylation. Consistent with this, in three PTEN (phosphatase and tensin homologue deleted on chromosome 10)-null tumour cell lines (in which the lipid phosphatase PTEN that normally restrains the Akt pathway is absent and Akt is thus hyperactivated), AMPK was resistant to activation by A769662. However, full AMPK activation could be restored by pharmacological inhibition of Akt, or by re-expression of active PTEN. We also show that inhibition of Thr(172) phosphorylation is due to interaction of the phosphorylated ST loop with basic side chains within the αC-helix of the kinase domain. Our findings reveal that a previously unrecognized effect of hyperactivation of Akt in tumour cells is to restrain activation of the LKB1 (liver kinase B1)–AMPK pathway, which would otherwise inhibit cell growth and proliferation

Biological Control of Fenusa pusilla (Hymenoptera: Tenthredinidae) in the Northeastern United States: A Thirty-four Year Perspective on Efficacy

Parasitoid releases against the birch leafminer Fenusa pusilla (Lepeletier) (Hymenoptera: Tenthredinidae) in eastern North America began in 1974, with releases in eastern Canada, followed by others in the Middle Atlantic States and New England. Of 4 parasitoids released, only 1, the ichneumonid Lathrolestes nigricollis (Thompson), established and spread widely. Studies of its preliminary impacts were made in several locations in the 1980s and 1990s, but full impact of the parasitoid on host density was not yet achieved in that period. Here we report results of surveys in 7 states (MA, CT, RI, NY, PA, NJ, DE) in 2007 documenting the current birch leaf miner levels (as % of leaves mined in spring) and parasitism. Survey results show that the pest has declined dramatically to barely detectable levels in 5 states (MA, CT, RI, NY, PA) but that in southern NJ, the pest remains abundant (ca 50% leaves mined) despite significant parasitism levels. Survey results, in context with previous evaluations made when populations were still declining, show that the project has been completely successful in much of the northeastern USA, but that there is a southern limit to efficacy in mid-New Jersey. Possible reasons for lack of control in this area, in contrast to high levels of control elsewhere, are discussed

A process model of the formation of spatial presence experiences

In order to bridge interdisciplinary differences in Presence research and to establish connections between Presence and “older” concepts of psychology and communication, a theoretical model of the formation of Spatial Presence is proposed. It is applicable to the exposure to different media and intended to unify the existing efforts to develop a theory of Presence. The model includes assumptions about attention allocation, mental models, and involvement, and considers the role of media factors and user characteristics as well, thus incorporating much previous work. It is argued that a commonly accepted model of Spatial Presence is the only solution to secure further progress within the international, interdisciplinary and multiple-paradigm community of Presence research

LKB1 and AMPK and the cancer-metabolism link - ten years after

The identification of a complex containing the tumor suppressor LKB1 as the critical upstream kinase required for the activation of AMP-activated protein kinase (AMPK) by metabolic stress was reported in an article in Journal of Biology in 2003. This finding represented the first clear link between AMPK and cancer. Here we briefly discuss how this discovery came about, and describe some of the insights, especially into the role of AMPK in cancer, that have followed from it. In September 2003, our groups published a joint paper [1] in Journal of Biology (now BMC Biology) that identified the long-sought and elusive upstream kinase acting on AMP-activated protein kinase (AMPK) as a complex containing LKB1, a known tumor suppressor. Similar findings were reported at about the same time by David Carling and Marian Carlson [2] and by Reuben Shaw and Lew Cantley [3]; at the time of writing these three papers have received between them a total of over 2,000 citations. These findings provided a direct link between a protein kinase, AMPK, which at the time was mainly associated with regulation of metabolism, and another protein kinase, LKB1, which was known from genetic studies to be a tumor suppressor. While the idea that cancer is in part a metabolic disorder (first suggested by Warburg in the 1920s [4]) is well recognized today [5], this was not the case in 2003, and our paper perhaps contributed towards its renaissance. The aim of this short review is to recall how we made the original finding, and to discuss some of the directions that these findings have taken the field in the ensuing ten years

CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability

A characteristic of memory T (TM) cells is their ability to mount faster and stronger responses to reinfection than naïve T (TN) cells do in response to an initial infection. However, the mechanisms that allow this rapid recall are not completely understood. We found that CD8 TM cells have more mitochondrial mass than CD8 TN cells and, that upon activation, the resulting secondary effector T (TE) cells proliferate more quickly, produce more cytokines, and maintain greater ATP levels than primary effector T cells. We also found that after activation, TM cells increase oxidative phosphorylation and aerobic glycolysis and sustain this increase to a greater extent than TN cells, suggesting that greater mitochondrial mass in TM cells not only promotes oxidative capacity, but also glycolytic capacity. We show that mitochondrial ATP is essential for the rapid induction of glycolysis in response to activation and the initiation of proliferation of both TN and TM cells. We also found that fatty acid oxidation is needed for TM cells to rapidly respond upon restimulation. Finally, we show that dissociation of the glycolysis enzyme hexokinase from mitochondria impairs proliferation and blocks the rapid induction of glycolysis upon T-cell receptor stimulation in TM cells. Our results demonstrate that greater mitochondrial mass endows TM cells with a bioenergetic advantage that underlies their ability to rapidly recall in response to reinfection

Local adaptation shapes functional traits and resource allocation in black spruce

Climate change is rapidly altering weather patterns, resulting in shifts in climatic zones. The survival of trees in specific locations depends on their functional traits. Local populations exhibit trait adaptations that ensure their survival and accomplishment of growth and reproduction processes during the growing season. Studying these traits offers valuable insights into species responses to present and future environmental conditions, aiding the implementation of measures to ensure forest resilience and productivity. This study investigates the variability in functional traits among five black spruce ( Picea mariana (Mill.) B.S.P.) provenances originating from a latitudinal gradient along the boreal forest, and planted in a common garden in Quebec, Canada. We examined differences in bud phenology, growth performance, lifetime first reproduction, and the impact of a late-frost event on tree growth and phenological adjustments. The findings revealed that trees from northern sites exhibit earlier budbreak, lower growth increments, and reach reproductive maturity earlier than those from southern sites. Late-frost damage affected growth performance, but no phenological adjustment was observed in the successive year. Local adaptation in the functional traits may lead to maladaptation of black spruce under future climate conditions or serve as a potent evolutionary force promoting rapid adaptation under changing environmental conditions

Postural Hypo-Reactivity in Autism is Contingent on Development and Visual Environment: A Fully Immersive Virtual Reality Study

Although atypical motor behaviors have been associated with autism, investigations regarding their possible origins are scarce. This study assessed the visual and vestibular components involved in atypical postural reactivity in autism. Postural reactivity and stability were measured for younger (12–15 years) and older (16–33 years) autistic participants in response to a virtual tunnel oscillating at different frequencies. At the highest oscillation frequency, younger autistic participants showed significantly less instability compared to younger typically-developing participants; no such group differences were evidenced for older participants. Additionally, no significant differences in postural behavior were found between all 4 groups when presented with static or without visual information. Results confirm that postural hypo-reactivity to visual information is present in autism, but is contingent on both visual environment and development

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase

In Vivo Characterization of Glutamine Metabolism Identifies Therapeutic Targets in Clear Cell Renal Cell Carcinoma

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase