bluuebunny/crossref_metadata_2025 huggingface dataset:
Why a Diet Rich in Seafood Is Healthy
Authors: Gough Nancy R.
Published: December 2006

Omega-3 fatty acids, which are found in marine organisms, are known for their beneficial health effects. One mechanism for their antiinflammatory effects is competitive inhibition of the enzymatic activity of cyclooxygenase (COX), which is the rate-limiting enzyme in the biosynthesis of prostaglandins. Massaro
et al
. report that exposure of endothelial cells to the omega-3 fatty acid docosahexaenoate (DHA) for periods long enough to allow incorporation of this lipid into cellular membranes inhibits the activation of nuclear factor κB (NF-κB) and subsequently
COX-2
expression and prostaglandin production in response to proinflammatory signals. Treatment of human saphenous vein endothelial cells (HSVECs) with DHA for up to 48 hours maximally inhibited COX activation in response to subsequent exposure of the cells to interleukin 1α (IL-1α) or a phorbol ester. Western blot and Northern analysis showed that DHA treatment inhibited the IL-1α- or phorbol ester-stimulated expression and abundance of COX-2 (the inducible isoform) without affecting that of COX-1 (the constitutively expressed isoform). Reporter gene analysis demonstrated that DHA-mediated inhibition of COX-2 required the NF-κB binding site in the COX-2 promoter, and DHA pretreatment decreased IL-1α stimulation of NF-κB DNA binding (measured by electrophoretic mobility shift assay) and nuclear translocation (measured by cell fractionation followed by Western blotting). DHA treatment inhibited several steps in the pathway activated by IL-1α that leads to NF-κB activation. In cells treated with DHA, subsequent responses to IL-1α showed (i) decreased extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation but no change in activation of p38 mitogen-activated protein kinase (p38 MAPK), (ii) decreased reactive oxygen species production through inhibition of membrane association of the p47
phox
subunit of NADPH oxidase, and (iii) decreased membrane association of protein kinase Cε (PKCε) but not PKCα or PKCζ. Thus, it appears that the long-term beneficial effects of omega-3 fatty acids may be due to alteration of membrane lipid composition leading to reduced signaling in response to inflammatory stimuli.

M. Massaro, A. Habib, L. Lubrano, S. Del Turco, G. Lazzerini, T. Bourcier, B. B. Weksler, R. De Caterina, The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKCε inhibition.
Proc. Natl. Acad. Sci. U.S.A.
103
, 15184-15189 (2006).
[Abstract]
[Full Text]
Innately Malignant?
Authors: Adler Elizabeth M.
Published: December 2006

Chien
et al
. investigated pathways downstream of Ras-related guanosine triphosphatase B (RalB), which has been implicated in Ras-induced oncogenic transformation, and unearthed a link between oncogenesis and the innate immune response. An RNAi screen revealed that, like RalB depletion, depletion of Sec5 (a component of the exocyst complex, which is involved in tethering secretory vesicles to the plasma membrane) induced apoptosis in human tumor-derived cell lines but not in nontumorigenic epithelial cells. Analysis of the exocyst complex revealed the atypical IκB kinase TBK1 (Tank binding kinase 1, a known component of the innate immune response), which bound to Sec5 in in vitro assays and coimmunoprecipitated with it from HEK293 cells; moreover, TBK1 depletion stimulated apoptosis in tumor-derived cells. Mouse embryo fibroblasts (MEFs) lacking TBK1 were more likely than wild-type MEFs to undergo apoptosis in response to oncogenic K-ras and were less likely to undergo oncogenic transformation, whereas expression of catalytically inactive TBK1 in conjunction with oncogenic K-ras promoted apoptosis. A constitutively active form of Ral promoted TBK1 association with Sec5, enhanced TBK1-dependent phosphorylation of IRF-3 (interferon regulatory factor-3), and stimulated Sec5- and TBK1-dependent nuclear translocation of IRF-3. Both polyinosine-polycytidylic acid [poly(I:C), a mimic of viral dsRNA] and Sendai virus activated endogenous RalB in human bronchial epithelial cells; Sec5 depletion inhibited poly(I:C)- and Sendai virus-dependent translocation of IRF-3 and activation of target genes.
Drosophila
with a single copy of dSec5 or a hypomorphic mutation of dRal showed an attenuated response to fungus. Thus, the RalB-Sec5-TBK1 connection appears to link innate immune signaling to cancer cell survival. Mantovani and Balkwill discuss the results in the context of the known relationship between inflammation and cancer.

Y. Chien, S. Kim, R. Bumeister, Y.-M. Loo, S. W. Kwon, C. L. Johnson, M. G. Balakireva, Y. Romeo, L. Kopelovich, M. Gale Jr., C. Yeaman, J. H. Camonis, Y. Zhao, M. A. White, RalB GTPase-mediated activation of the IκB family kinase TBK1 couples innate immune signaling to tumor cell survival.
Cell
127
, 157-170 (2006).
[PubMed]

A. Mantovani, F. Balkwill, RalB signaling: A bridge between inflammation and cancer.
Cell
127
, 42-44 (2006).
[PubMed]
No NFAT, No Fat
Authors: Ray L. Bryan
Published: December 2006

Obesity is a common health problem in the United States and other countries, so intensive efforts are focused on understanding the signaling pathways that control metabolism and the growth and physiology of fat-storing cells (adipocytes). Noting that there are similarities in obesity and inflammatory responses, Yang
et al
. explored the role of members of the NFAT (nuclear factor of activated T cells) family for a possible role in regulating glucose homeostasis, insulin sensitivity, and obesity. NFAT proteins are best known as critical mediators for expression of cytokines in response to activation of T cells in the immune system. However, Yang
et al
. found that increased expression of NFATc2 and NFATc4 was associated with differentiation of cultured mouse 3T3-L1 adipocytes or with obesity in a mouse model. Consistent with such effects, NFATc4 is expressed primarily in nonimmune tissues, including muscle and fat. Double knockout mice lacking NFATc2 and NFATc4 (Nfatc2
−/−
Nfatc4
−/−
mice) were resistant to obesity caused by ingestion of a high-fat diet and accumulated fewer adipocytes than did normal animals (regardless of their diet). The Nfatc2
−/−
Nfatc4
−/−
animals also showed a higher metabolic rate, greater heat production, more effective control of blood glucose after oral administration of glucose, and increased sensitivity to insulin. Adiopocytes secrete regulatory peptides (adipokines) and, similar to their effects on cytokine production in the immune system, the NFAT proteins appeared to regulate expression of genes encoding adipokines in adipocytes. Chromatin immunoprecipitation experiments showed association of NFATc2 with the promoter of the gene encoding the adipokine resistin. Pharmacological blockade of NFAT activation also reduced expression of resistin mRNA. NFAT has been previously implicated in roles outside the immune system, including heart development and neural pathfinding. The new work shows an even broader repertoire for the NFAT proteins that includes key roles in metabolic pathogenesis and expression of adipokine genes.

T. T. C. Yang, H. Y. Suk, X. Y. Yang, O. Olabisi, R. Y. L. Yu, J. Durand, L. A. Jelicks, J.-Y. Kim, P. E. Scherer, Y. Wang, Y. Feng, L. Rossetti, I. A. Graef, G. R. Crabtree, C.-W. Chow, Role of transcription factor NFAT in glucose and insulin homeostasis.
Mol. Cell. Biol.
26
, 7372-7387 (2006).
[Abstract]
[Full Text]
Not-So-Simple Switches
Authors: Vinson Valda
Published: December 2006

Riboswitches are structured RNAs that bind metabolites and, dependent on this binding, control gene expression. In most cases, the metabolite binding acts as a simple "on-off" switch. Now Sudarsan
et al
. report tandem riboswitch architectures that facilitate more sophisticated control. The 5′ untranslated region of
Bacillus clausii
metE RNA includes two riboswitches that respond independently to two different metabolites to function as a two-input Boolean NOR logic gate.

N. Sudarsan, M. C. Hammond, K. F. Block, R. Welz, J. E. Barrick, A. Roth, R. R. Breaker, Tandem riboswitch architectures exhibit complex gene control functions.
Science
314
, 300-304 (2006).
[Abstract]
[Full Text]
Dealing with DNA Damage
Authors: Ray L. Bryan
Published: December 2006

For an organism to remain healthy, cells with damaged DNA must either pause in the cell cycle for a repair job or succumb to elimination by apoptosis. Huang
et al
. provide a mechanism through which cells with genomic damage may switch between these alternative fates. DNA damage activates a checkpoint signaling mechanism that arrests the cell cycle in part by inhibiting activity of cyclin-dependent kinase 2 (CDK2). The authors now find that CDK2 may also couple to the machinery controlling cell death. Normally, the transcription factor FOXO1 is phosphorylated by CDK2. In cells with extensive DNA damage, reduced phosphorylation of FOXO1 allows its translocation to the nucleus, where it enhances expression of apoptosis-inducing genes.

H. Huang, K. M. Regan, Z. Lou, J. Chen, D. J. Tindall, CDK-2 dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage.
Science
314
, 294-297 (2006).
[Abstract]
[Full Text]

J. Bartek, J. Lukas, Balancing life-or-death decisions.
Science
314
, 261-262 (2006).
[Abstract]
[Full Text]
Branching Out
Authors: Kiberstis Paula A.
Published: December 2006

At puberty, the female mammary gland is transformed from a simple epithelial tubule into an elaborate ductal tree. Underlying this global change in tissue architecture are changes in the behavior of individual cells. Certain cells within the tubules are instructed to branch, whereas their neighbors, only a few cell diameters away, are not. Using a micropatterning approach to engineer mouse mammary epithelial tubules in culture, Nelson
et al
. show that the position of branching depends on the initial tubule geometry and is determined by a local minimum in the concentration gradient of autocrine inhibitory morphogens, including transforming growth factor-β.

C. M. Nelson, M. M. VanDuijn, J. L. Inman, D. A. Fletcher, M. J. Bissell, Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures.
Science
314
, 298-300 (2006).
[Abstract]
[Full Text]
Rethinking Viral Resistance
Authors: Simpson Stephen
Published: December 2006

In their investigations of herpes simplex encephalitis, Casrouge
et al
. found that a single gene defect can impair resistance to the causative herpes simplex virus but not others. The rare autosomal recessive mutation was present in a conserved gene encoding the endoplasmic reticulum membrane protein UNC-93B, which is thought to be involved in the cellular antiviral immune response. Cells from these subjects displayed defective response of some interferon genes, which would explain the children’s severe defect in controlling viral replication. In contrast, the seemingly robust immunity of the subjects to other pathogens suggests, rather unexpectedly, that a single gene defect can lead to a pathogen-specific form of immunodeficiency.

A. Casrouge, S.-Y. Zhang, C. Eidenschenk, E. Jouanguy, A. Puel, K. Yang, A. Alcais, C. Picard, N. Mahfoufi, N. Nicolas, L. Lorenzo, S. Plancoulaine, B. Sénéchal, F. Geissmann, K. Tabeta, K. Hoebe, X. Du, R. L. Miller, B. Héron, C. Mignot, T. B. de Villemeur, P. Lebon, O. Dulac, F. Rozenberg, B. Beutler, M. Tardieu, L. Abel, J.-L. Casanova, Herpes simplex virus encephalitis in human UNC-93B deficiency.
Science
314
, 308-312 (2006).
[Abstract]
[Full Text]
Caspase Inhibitors Promote Alternative Cell Death Pathways
Authors: Vandenabeele Peter , Vanden Berghe Tom , Festjens Nele
Published: December 2006

The use of caspase inhibitors has revealed the existence of alternative backup cell death programs for apoptosis. The broad-spectrum caspase inhibitor zVAD-fmk modulates the three major types of cell death. Addition of zVAD-fmk blocks apoptotic cell death, sensitizes cells to necrotic cell death, and induces autophagic cell death. Several studies have shown a crucial role for the kinase RIP1 and the adenosine nucleotide translocator (ANT)–cyclophilin D (CypD) complex in necrotic cell death. The underlying mechanism of zVAD-fmk–mediated sensitization to necrotic cell death involves the inhibition of caspase-8–mediated proteolysis of RIP1 and disturbance of the ANT-CypD interaction. RIP1 is also involved in autophagic cell death. Caspase inhibitors and knockdown studies have revealed negative roles for catalase and caspase-8 in autophagic cell death. The positive role of RIP1 and the negative role of caspase-8 in both necrotic and autophagic cell death suggest that the pathways of these two types of cell death are interconnected. Necrotic cell death represents a rapid cellular response involving mitochondrial reactive oxygen species (ROS) production, decreased adenosine triphosphate concentration, and other cellular insults, whereas autophagic cell death first starts as a survival attempt by cleaning up ROS-damaged mitochondria. However, when this process occurs in excess, autophagy itself becomes cytotoxic and eventually leads to autophagic cell death. A better understanding of the molecular mechanisms of these alternative cell death pathways may provide therapeutic tools to combat cell death associated with neurodegenerative diseases, ischemia-reperfusion pathologies, and infectious diseases, and may also facilitate the development of alternative cytotoxic strategies in cancer treatment.
Superantigens: Supersignalers?
Authors: Zamoyska Rose
Published: December 2006

Some bacterial and viral proteins are potent activators of the immune response, earning them the title of superantigens (SAgs). Infection with pathogens containing these proteins can produce massive T cell activation and can result in various potentially fatal conditions, such as toxic shock and food poisoning. Unlike conventional peptide antigens, SAgs bind promiscuously to the external faces of class II major histocompatibility complex (MHC) molecules and families of T cell receptors (TCRs), thereby activating large numbers of T cells simultaneously. The manner in which SAgs bind MHC and TCR differs from the way in which peptide antigens interact with these structures. Nevertheless, because they simultaneously engage MHC and TCR, SAgs were assumed to activate T cells through the canonical signaling pathway that has been described for T cell activation by TCR engagement of peptide-MHC complexes. However, recent research shows that SAgs also activate an alternative signaling pathway in T cells. This study shows that SAgs can stimulate T cells in the absence of the Src family kinase, Lck, by activating a heterotrimeric guanine nucleotide–binding protein (G protein), Gα
11
. Gα
11
activates phospholipase C–β (PLC-β), rather than the more abundant PLC-γ1, and, by this means, links SAg signaling to the phosphatidylinositol and protein kinase C signaling pathways. The discovery of a signaling pathway specifically activated by SAgs, and not by conventional peptide antigens, opens the possibility of developing therapeutic reagents that may help control diseases caused by these agents.
Memories of the Proteasome
Authors: Ray L. Bryan
Published: December 2006

The process of long-term potentiation (LTP) in the hippocampus­­­--a stable change in synaptic strength after stimulation of a neuronal circuit--is thought to provide a cellular mechanism for learning and memory. Late-phase LTP (L-LTP), the longest lasting form of such plasticity, is inhibited when protein synthesis is blocked, which has led investigators to propose that there may be newly synthesized proteins that account for the changes in cellular function. In the most simple terms, one might expect, then, that inhibition of the proteasome, which mediates degradation of proteins tagged with the peptide ubiquitin, might enhance L-LTP. In keeping with some earlier indications, however, Fonseca
et al
. found that pharmacological inhibition of the proteasome inhibited L-LTP in cultured hippocampal slices from rat brain. Unexpectedly, if a protein synthesis inhibitor was applied along with the proteasome inhibitor, L-LTP was restored. The authors propose that rather than an absolute requirement for generation of new proteins, it may be a balance of degradation and synthesis that is most important to enable long-lasting changes in synaptic plasticity. Not discussed by the authors is the additional possibility that recently described more direct effects of the proteasome on transcription could factor into the explanation for these results.

R. Fonseca, R. M. Vabulas, F. U. Hartl, T. Bonhoeffer, U. V. Nägerl, A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP.
Neuron
52
, 239-245 (2006).
[PubMed]
Regulating ROS Metabolism
Authors: Adler Elizabeth M.
Published: December 2006

Peroxisome proliferator-activated

receptor γ (PPARγ) coactivator 1α (PGC-1α), a transcriptional coactivator implicated in transducing physiological stimuli into metabolic programs, stimulates mitochondrial biogenesis and mitochondrial respiration, which generates reactive oxygen species (ROS). St-Pierre
et al
. exposed 10T1/2 cells to hydrogen peroxide (H
2
O
2
) and found that
PGC-1α
expression was increased along with that of mRNAs encoding ROS-detoxifying enzymes and mitochondrial uncouplers (activity of which limits ROS production). RNAi directed against PGC-1α decreased basal and H
2
O
2
-induced expression of
PGC-1α
and various components of the ROS defense system. Expression of superoxide dismutase 1 and 2 and catalase was reduced in the hearts and brains of
PGC-1α
-null mice compared with wild-type mice. Moreover, fibroblasts derived from
PGC-1α
-null mice had increased ROS compared with fibroblasts from wild-type mice--a decrease in H
2
O
2
-dependent induction of components of the ROS defense system--and were more vulnerable to H
2
O
2
. Experiments involving mutation of the cAMP response element (CRE), a CRE-binding protein (CREB) dominant-negative mutant, immunoblot analysis, and chromatin immunoprecipitation implicated CREB in the transcriptional activation of PGC-1α in response to oxidative stress.
PGC-1α
-null mice showed increased neurodegeneration in the substantia nigra in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) compared with wild-type mice and increased hippocampal neurodegeneration in response to kainic acid. Cultured striatal cells infected with PGC-1α adenovirus showed increased expression of
PGC-1α
and mRNA encoding ROS-detoxifying enzymes and increased survival when treated with paraquat or H
2
O
2
. Thus, the authors conclude that PGC-1α plays a critical role in regulating ROS metabolism and may present a target for therapeutic manipulation in neurodegenerative diseases associated with disordered ROS metabolism.

J. St-Pierre, S. Drori, M. Uldry, J. M. Silvaggi, J. Rhee, S. Jäger, C. Handschin, K. Zheng, J. Lin, W. Yang, D. K. Simon, R. Bachoo, B. M. Spiegelman, Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators.
Cell
127
, 397-408 (2006).
[Online Journal]
How to Get from IgM to IgG
Authors: Gough Nancy R.
Published: December 2006

Antibody-producing cells undergo a process of differentiation and class switch recombination (CSR) such that the antibodies produced start as immunoglobulin M (IgM) and then switch to IgG and IgA as the concentration of antigen changes and as the cells differentiate. Omori
et al
. show that CSR in antibody-secreting cells is inhibited in mice in which the lipid phosphatase
pten
gene has been selectively inactivated in B cells (b
Pten
−/−
). Flow cytometry analysis of splenocytes from immunized mice showed that the b
Pten
−/−
mice formed germinal centers (sites of B cell differentiation) but did not exhibit the class switch from IgM-producing cells to IgG-producing cells that was observed for the wild-type mice. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) nonselectively, or of the PI3Kδ isoform selectively, resulted in enhanced production of IgG antibodies from wild-type mice and restored the production of IgG antibodies from the b
Pten
−/−
cells. Inhibition of PI3Kδ allowed the wild-type cells to undergo CSR after the first cell division after exposure to antigenic stimulation, whereas in the absence of any inhibitors, the wild-type cells required at least three cell divisions before CSR was observed. Retroviral expression of constitutively active Akt also blocked CSR, and forced expression of nuclear-targeted Foxo1 transcription factor, the activity of which is inhibited by Akt, promoted CSR. Thus, PI3Kδ signaling through the Akt to inhibit Foxo1 appears to be required for inhibition of CSR. Indeed, the expression of the gene encoding activation-induced cytidine deaminase (AID), which is required for CSR, was decreased in cells expressing the constitutively active Akt. The authors suggest that when antigenic load is high, the activity of PI3K is high and CSR is inhibited to allow the IgM-producing cells to promote initial clearance of the antigen. As antigenic load decreases, PI3K stimulation also decreases, allowing CSR and the formation of specialized B cells producing different antibody isotypes.

S. A. Omori, M. H. Cato, A. Anzelon-Mills, K. D. Puri, M. Shapiro-Shelef, K. Calame, R. C. Rickert, Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling.
Immunity
25
, 545-557 (2006).
[PubMed]
Immune Response Regulation
Authors: Hurtley Stella M.
Published: December 2006

Mycobacterial heat shock proteins have been implicated in the way the host response to mycobacterial infection is finely balanced to control pathogen dissemination while preventing immunopathology. Constitutive overexpression of mycobacterial Hsp70 (myHsp70) enhances mycobacterial clearance in mouse models, and Hsps can promote antitumor and antiviral immune responses. Human dendritic cells pulsed with myHsp70 generate potent antigen-specific cytotoxic T cell responses, which are dependent on a calcium-signaling cascade. Floto
et al
. now show that this critical function of myHsp70 is dependent on signaling through the HIV coreceptor, CCR5.

R. A. Floto, P. A. MacAry, J. M. Boname, T. S. Mien, B. Kampmann, J. R. Hair, O. S. Huey, E. N. G. Houben, J. Pieters, C. Day, W. Oehlmann, M. Singh, K. G. C. Smith, P. J. Lehner, Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5.
Science
314
, 454-458 (2006).
[Abstract]
[Full Text]
Palmitoylation of Ligands, Receptors, and Intracellular Signaling Molecules
Authors: Resh Marilyn D.
Published: December 2006

Palmitate, a 16-carbon saturated fatty acid, is attached to more than 100 proteins. Modification of proteins by palmitate has pleiotropic effects on protein function. Palmitoylation can influence membrane binding and membrane targeting of the modified proteins. In particular, many palmitoylated proteins concentrate in lipid rafts, and enrichment in rafts is required for efficient signal transduction. This Review focuses on the multiple effects of palmitoylation on the localization and function of ligands, receptors, and intracellular signaling proteins. Palmitoylation regulates the trafficking and function of transmembrane proteins such as ion channels, neurotransmitter receptors, heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors, and integrins. In addition, immune receptor signaling relies on protein palmitoylation at many levels, including palmitoylated co-receptors, Src family kinases, and adaptor or scaffolding proteins. The localization and signaling capacities of Ras and G proteins are modulated by dynamic protein palmitoylation. Cycles of palmitoylation and depalmitoylation allow H-Ras and G protein α subunits to reversibly bind to and signal from different intracellular cell membranes. Moreover, secreted ligands such as Hedgehog, Wingless, and Spitz use palmitoylation to regulate the extent of long- or short-range signaling. Finally, palmitoylation can alter signaling protein function by direct effects on enzymatic activity and substrate specificity. The identification of the palmitoyl acyltransferases has provided new insights into the biochemistry of this posttranslational process and permitted new substrates to be identified.
TLR8 in the Developing Mouse Nervous System
Authors: Gough Nancy R.
Published: December 2006

In the fruit fly, Toll receptors function during embryogenesis to specify the dorsal-ventral axis in the developing nervous system. In mammals, Toll-like receptors (TLRs) are best known as initiators of the innate immune response through activation of the transcription factor nuclear factor κB (NF-κB). Ma
et al
. show that TLR8 is dynamically expressed in developing mouse brain and peripheral ganglia. Cultured cortical neurons from embryonic day 16 mice possessed abundant cytosolic TLR8 in the perinuclear region, neurites, and growth cones. Application of a membrane-permeable agonist, resiquinod (R-848), resulted in shorter neurites and an increase in cell death. Cell death, but not the decreased neurite length, was blocked by caspase inhibition. Transduction of a function-blocking antibody against TLR8 partially prevented the R-848-mediated decrease in neurite length and decreased the activation of caspase-3. TLR8 did not activate NF-κB, nor did it promote other hallmarks of activation of the canonical TLR signaling pathway, which suggests that in neurons TLR8 acts through a different pathway. Twenty-four-hour exposures to R-848, which is the time when substantial effects on neurite outgrowth and cell death were noted, caused decreased abundance of IκBα (an inhibitor of the NF-κB pathways as well as an NF-κB-independent transcriptional regulator) and IRAK-4 (interleukin-1 receptor-associated kinase 4). Thus, TLR8 may be a negative regulator of neurite extension and survival during embryogenesis through a noncanonical signaling pathway.

Y. Ma, J. Li, I. Chiu, Y. Wang, J. A. Sloane, J. Lü, B. Kosaras, R. L. Sidman, J. J. Volpe, T. Vartanian, Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis.
J. Cell Biol.
175
, 209-215 (2006).
[Abstract]
[Full Text]
Removing Proinflammatory Signals
Authors: Gough Nancy R.
Published: December 2006

Response to injury or infection involves a proinflammatory phase and an antiinflammatory or resolution phase. Ariel
et al
. used mice deficient for the chemokine receptor CCR5, which binds chemokines CCL3, CCL4, and CCL5, to show that CCR5 contributes to the clearance of these chemokines during mouse peritonitis. Peritoneal exudates from
ccr5
−/−
mice with peritonitis had higher concentrations of CCL3 and CCL5 and exhibited decreased abundance of polymorphonuclear neutrophils (PMNs) and an increased percentage of macrophage-PMN conjugates than did exudates from wild-type mice with peritonitis. Cultured human PMNs spontaneously undergo apoptosis in the absence of added survival factors, and late apoptotic cells exhibited increased CCR5 abundance at the cell surface compared with freshly isolated cells; this increase was blocked by caspase inhibitors that also blocked apoptosis. Exposure of the cells to lipid mediators that contribute to inflammation resolution also stimulated CCR5 abundance at the cell surface without altering the percentage of apoptotic cells, suggesting that these lipids stimulate trafficking of CCR5 to the surface of apoptotic cells. T cells are also cleared by macrophages and, using either isolated human T cells or Jurkat T cell lines, the authors showed that stimuli that trigger apoptosis also increased the percentage of cells on which CCR5 could be detected. However, this increase was noted only for cells in the late stages of apoptosis, not live cells or cells in the early stages of apoptosis, in which abundance of CCR5 was low. The up-regulated CCR5 appeared to have a higher affinity for CCL4 than that of CCR5 on live cells, and CCL4 appeared to bind in clusters on the surface of the apoptotic cells. The increase in CCR5 at the surface of the T cells was also blocked by caspase inhibition, suggesting that the apoptotic cascade contributes to this process. The authors propose that PMNs and T cells initially attracted to the site of inflammation by chemokines eventually undergo apoptosis, resulting in increased cell surface CCR5, which binds the inflammatory chemokines. As these apoptotic cells are engulfed by the macrophages, the inflammatory chemokines are removed from the site of injury, allowing healing to occur.

A. Ariel, G. Fredman, Y.-P. Sun, A. Kantarci, T. E. Van Dyke, A. D. Luster, C. N. Serhan, Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression.
Nat. Immunol.
7
, 1209-1216 (2006).
[PubMed]
Deadly Redundancy
Authors: Ray L. Bryan
Published: December 2006

Stimuli such as tumor necrosis factor (TNF) activate cell death or apoptosis by activating the cysteine proteases known as caspases. Such receptor stimulation enhances formation of the apoptosome, a protein complex that allows activation of caspase 9. But is this the only way to skin the cat? Evidently not, according to an international collaboration of leading labs in the apoptosis field. Gyrd-Hansen
et al
. used mouse embryo fibroblasts (MEFs) lacking components of apoptotic pathways to show that the cells required caspase 9 to undergo TNF-induced death but did not need the protein Apaf-1, a component of the apoptosome required for activation of caspase 9 by that complex. Activation of caspase 9 in this Apaf-1-independent context appeared to require its cleavage and activation by another caspase, caspase 8. Further studies with knockout MEFs showed that permeabilization of mitochondria was also not required for this apoptosome-independent cell death in response to TNF. Instead, cell death was associated with permeabilization of lysosomal membranes, an alternative means of cell destruction that depends on release of lysosomal cathepsins. Cells with complete apoptotic machinery appeared to use both the mitochondrial and the lysosomal pathways to execute cell death in response to TNF. Protection from TNF-induced death was achieved only after gene ablation or pharmacological treatments that inhibited both pathways. The authors propose that such redundant signaling of apoptosis may be common and that death-resistant cancer cells may have perturbations in multiple pathways. Understanding the underlying pathways thus may allow more effective strategies to deliver therapeutic treatments that reactivate cell death in tumor cells.

M. Gyrd-Hansen, T. Farkas, N. Fehrenbacher, L. Bastholm, M. Høyer-Hansen, F. Elling, D. Wallach, R. Flavell, G. Kroemer, J. Nylandsted, M. Jäättelä, Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9.
Mol. Cell. Biol.
26
, 7880-7891 (2006).
[Abstract]
[Full Text]
Herding Olfactory Axons
Authors: Hines Pamela J.
Published: December 2006

In the mammalian olfactory system, sensory neurons each express only one odorant receptor, and the axons from neurons that express the same odorant receptor somehow manage to converge on a single glomerulus in the brain. Imai
et al
. have now brought both clarity and complexity to the problem. Although axon guidance was thought to depend solely on the odorant receptor, it now seems that a separate signaling system involving cyclic adenosine monophosphate (cAMP) contributes to guiding axons to a general position along the anterior-posterior axis.

T. Imai, M. Suzuki, H. Sakano, Odorant receptor-derived cAMP signals direct axonal targeting.
Science
314
, 657-661 (2006).
[Abstract]
[Full Text]

C. Dulac, Charting olfactory maps.
Science
314
, 606-607 (2006).
[Abstract]
[Full Text]
Formation of Ion Channel Complexes
Authors: Stern Peter
Published: December 2006

Large-conductance Ca
2+
- and voltage-activated K
+
(BK
Ca
) channels play diverse and critical roles in a number of neuronal functions and provide a link between membrane potential and intracellular calcium. Previous studies suggested a tight functional coupling between BK channels and certain classes of voltage-gated Ca
2+
channels in neurons. However, the molecular basis for such coupling has been unclear. Berkefeld
et al
. now confirm that BK
Ca
channels form bimolecular complexes with voltage-gated Ca
2+
channels. This bimolecular complex formation provides the basis for the fast and localized Ca
2+
-activated K
+
signaling that controls neuronal firing patterns and release of hormones and transmitters in the central nervous system.

H. Berkefeld, C. A. Sailer, W. Bildl, V. Rohde, J.-O. Thumfart, S. Eble, N. Klugbauer, E. Reisinger, J. Bischofberger, D. Oliver, H.-G. Knaus, U. Schulte, B. Fakler, BK
Ca
-Cav channel complexes mediate rapid and localized Ca
2+
-activated K
+
signaling.
Science
314
, 615-620 (2006).
[Abstract]
[Full Text]
Alzheimer’s Enzyme and Myelination
Authors: Hurtley Stella M.
Published: December 2006

β-secretase activity is crucial in the production of pathological β-amyloid in Alzheimer's disease (AD). However, its role in normal physiology is unclear, especially given the absence of an obvious phenotype in a knockout mouse for BACE1 (beta-site amyloid precursor protein-cleaving enzyme 1). Willem
et al
. found that BACE1 (but not its close homolog BACE2) is required for neuregulin (NRG)-mediated peripheral nerve myelination. NRG1 was an in vivo substrate of BACE1, and the BACE-1 knockout mouse fully phenocopied hypomyelination observed in NRG1 heterozygous mutant mice. Thus, BACE-1 plays a physiological role during development in myelination.

M. Willem, A. N. Garratt, B. Novak, M. Citron, S. Kaufmann, A. Rittger, B. DeStrooper, P. Saftig, C. Birchmeier, C. Haass, Control of peripheral nerve myelination by the β-secretase BACE1.
Science
314
, 664-666 (2006).
[Abstract]
[Full Text]

C. Glabe, Avoiding collateral damage in Alzheimer’s disease treatment.
Science
314
, 602-603 (2006).
[Abstract]
[Full Text]
Stress-ING Out: Phosphoinositides Mediate the Cellular Stress Response
Authors: Bunce Matthew W. , Gonzales Michael L. , Anderson Richard A.
Published: December 2006

Phosphoinositides regulate numerous cellular processes required for growth, proliferation, and motility. Whereas phosphoinositide signal transduction pathways within the cytosol have been well characterized, nuclear signaling pathways remain poorly understood. Accumulating experimental data have now started to uncover critical functions for nuclear phosphoinositides. In particular, phosphoinositides modulate the activity of the tumor suppressor protein ING2 in response to extracellular stress. These findings highlight a previously uncharacterized function for phosphoinositides and implicate their metabolism in signaling pathways critical for cell survival.
Channel to the Nucleus?
Authors: Adler Elizabeth M.
Published: December 2006

Gomez-Ospina
et al
. provide evidence for an intriguing mechanism whereby voltage-dependent calcium channels modulate gene transcription. Calcium entry through voltage-gated channels in the plasma membrane provides a link between electrical activity and changes in gene expression. Gomez-Ospina
et al
. found that, whereas an antibody that recognized the full-length Ca
v
1.2 calcium channel localized to membrane and cytosolic fractions of rat brain cortex, an antibody that recognized the C-terminal fragment, which is proteolytically cleaved, appeared in the nucleus. The C-terminal fragment was abundant in nuclei of GABAergic neurons; moreover, nuclear fluorescence was apparent in neurons or glioblastoma cells expressing a construct in which the Ca
v
1.2 C terminus was fluorescently labeled. Treatments aimed at lowering cytoplasmic calcium increased nuclear abundance of the Ca
v
1.2 fragment, whereas treatments that increase intracellular calcium decreased it. The Ca
v
1.2 fragment immunoprecipitated with p54(nrb)/NonO, a nuclear protein, and, when recruited to the promoter with a heterologous DNA binding domain, transcriptionally activated a gene reporter. Overexpression of the fragment, which the authors called calcium channel associated transcription regulator (CCAT), led to an increase in the expression of some endogenous genes and a decrease in the expression of others. CCAT overexpression increased the abundance of mRNA encoding the gap junction protein Cx31.1 and transcriptionally activated a reporter containing the
Cx31.1
promoter; chromatin immunoprecipitation analysis indicated that it associated with the
Cx31.1
promoter. Furthermore, decreasing the abundance of endogenous nuclear CCAT either by depolarization or with short hairpin RNA led to a decrease in transcription of the Cx31.1 reporter. Thus, the authors conclude that the proteolytically cleaved C terminus of Ca
v
1.2 translocates to the nucleus to act as a transcription factor.

N. Gomez-Ospina, F. Tsuruta, O. Barreto-Chang, L. Hu, R. Dolmetsch, The C terminus of the L-type voltage-gated calcium channel Ca
V
1.2 encodes a transcription factor.
Cell
127
, 591-606 (2006).
[PubMed]
A Complex Mode of Glucose Signaling
Authors: Adler Elizabeth M.
Published: December 2006

In
Arabidopsis
, hexokinase 1 (HXK1) acts as a glucose sensor to regulate gene expression and plant growth, a role distinct from its function in glycolysis; however, the mechanisms whereby HXK1 mediates glucose signaling have been unclear. After showing that a portion of
Arabidopsis
HXK was present in the nucleus, Cho
et al
. used proteomic and binary-interaction screens to identify two proteins--vacuolar H
+
-ATPase B1 (VHA-B1) and the 19
S
regulatory particle of proteasome subunit (RPT5B)--as nuclear-specific HXK1-interacting partners that formed a complex with HXK1. Genetic analysis revealed that
vha-B1
and
rpt5b
loss-of-function mutants resembled the HXK1
gin2
(
glucose-insensitive2
) mutant: All three mutants were insensitive to repression of cotyledon expansion, chlorophyll accumulation, and leaf and root development in response to high-glucose conditions and showed growth retardation compared with wild-type plants under low-light, low-nutrient conditions. The
gin2
-like phenotypes of the
vha-B1
and
rpt5b
mutants did not depend on loss of
HXK1
expression, HXK1 protein abundance, or reduction in glucose or fructose phosphorylation. Like
gin2
, the
vha-B1
and
rpt5b
mutants were insensitive to glucose-mediated repression of chlorophyll a/b binding protein (
CAB
) and carbonic anhydrase (
CAA
) gene expression. Chromatin immunoprecipitation analysis showed that the HXK1 complex bound to the
CAB2
promoter; this binding was reduced but not abolished in the
vha-B1
and
rpt5b
mutants. Thus, these three proteins appear to form a nucleus-specific complex that is critical to glucose-mediated regulation of gene transcription.

Y.-H. Cho, S.-D. Yoo, J. Sheen, Regulatory functions of nuclear hexokinase1 complex in glucose signaling.
Cell
127
, 579-589 (2006).
[PubMed]
OK, Everyone Keep Quiet
Authors: Adler Elizabeth M.
Published: December 2006

Glutamate transporters in glial cells and postsynaptic neurons are believed to accumulate synaptically released glutamate; however, the role of presynaptic glutamate transporters has been unclear (see Wadiche and von Gersdorff). Veruki
et al
. combined electrophysiological and pharmacological analysis to investigate the role of presynaptic glutamate transporters that mediate a prominent anion current uncoupled from glutamate uptake in retinal rod bipolar (RB) cells. After showing that glutamate transporter-mediated inward currents recorded from RB cells in rat retinal slices were largest and fastest when elicited by puffs of glutamate delivered near axon terminals in the inner plexiform layer, the authors confirmed the presynaptic location of the transporters by recording from isolated patches. Dual recordings from RB cells and synaptically connected AII amacrine cells, as well as a comparison of the time course of transporter currents recorded in RB cells in response to released glutamate to currents recorded from patches, indicated that transporters on RB cells were located perisynaptically (and farther from the site of release than were the postsynaptic receptors). Moreover, transporter currents in RB cells were activated not only by auto-released glutamate but also by glutamate released from neighboring RB cells. Transporter activation led to a decrease in transmitter release and thus a reduction in the postsynaptic response. Thus, presynaptic RB glutamate transporters appear to mediate both auto- and lateral inhibition of transmitter release.

M. L. Veruki, S. H. Mørkve, E. Hartveit, Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling.
Nat. Neurosci.
9
, 1388-1396 (2006).
[PubMed]

J. I. Wadiche, H. von Gersdorff, Long-distance signaling via presynaptic glutamate transporters.
Nat. Neurosci.
9
, 1352-1353 (2006).
[PubMed]
Neurite Extension and Membrane Trafficking
Authors: Hurtley Stella M.
Published: December 2006

Neurons extend processes (neurites) that can reach more than 1 meter in length. Formation of neurites requires both cytoskeletal remodeling and membrane transport. Shirane and Nakayama have now identified a protein, protrudin, that is essential for neurite extension triggered by nerve growth factor. Protrudin binds to and inhibits the activity of the protein Rab11, which functions as a molecular switch in membrane transport to the cell surface.

M. Shirane, K. I. Nakayama, Protrudin induces neurite formation by directional membrane trafficking.
Science
314
, 818-821 (2006).
[Abstract]
[Full Text]
Donning the Myelin Sheath
Authors: Hines Pamela J.
Published: December 2006

The myelin sheath electrically insulates axons and makes the conductance of neuronal impulses much more efficient. Chan
et al
. examined how the Schwann cells begin myelination of an axon. In neuronal cultures, a cell polarity protein, Par-3, localized to where the Schwann cell meets the axon and promoted the recruitment of the brain-derived neurotrophic factor (BDNF)-receptor to the junction between Schwann cell and neuron. BDNF-dependent signaling between axon and Schwann cell then ensures that myelination begins. This localized signaling arising from Par-3 polarity may help to ensure that the myelination begins at the right spot.

J. R. Chan, C. Jolicoeur, J. Yamauchi, J. Elliott, J. P. Fawcett, B. K. Ng, M. Cayouette, The polarity protein Par-3 directly interacts with p75
NTR
to regulate myelination.
Science
314
, 832-836 (2006).
[Abstract]
[Full Text]
Transferrin Receptor 2 as a Signaling Receptor
Authors: Gough Nancy R.
Published: December 2006

Transferrin receptor 2 (TfR2) is a transferrin-binding protein predominantly found in liver and intestine. Its abundance is generally opposite that of TfR1, a more ubiquitously present protein that is responsible for the uptake of iron into cells. Mutations in the gene encoding TfR2 (or knockout in mice) produce hemochromatosis and iron loading in the liver, suggesting a role for TfR2 in organismal iron homeostasis. Calzolari
et al
. used various methods to show that TfR2 was present in lipid raft domains in cultured HepG2 or K562 cells and that TfR2 coimmunoprecipitated with caveolin-1 and colocalized with the tetraspanin CD81. Although the protein was most abundant in the plasma membrane, where lipid raft association was increased in the presence of holotransferrin, the majority of intracellular TfR2 was in a compartment distinct from that in which TfR1 was found. Using sucrose gradient centrifugation, the authors separated exosomes from plasma membrane from lipid raft domains and found that TfR1 and TfR2 were present in exosome preparations, along with CD81. Surprisingly, TfR1 and TfR2 appeared to be present on separate populations of exosomes, in that isolated TfR2-positive exosomes did not cross-react with antibodies that recognized TfR1. When K562 cells were serum starved and then exposed to either human transferrin (binds to both TfR1 and TfR2) or bovine transferrin (binds only to TfR2) or to an antibody that cross-links TfR2, the cells exhibited a transient increase in extracellular signal-regulated kinase (ERK) phosphorylation, suggesting activation of the mitogen-activated protein kinase (MAPK) pathway. Cholesterol depletion inhibited the phosphorylation of ERK stimulated by the antibody against TfR2, suggesting that raft association was important for TfR2 to activate the MAPK pathway. This signaling connection supports the hypothesis that TfR2 serves as a sensor of hepatic iron status to regulate the activity of hepcidin, which is a hormone released by the liver that inhibits intestinal iron absorption and iron release by macrophages.

A. Calzolari, C. Raggi, S. Deaglio, N. M. Sposi, M. Stafsnes, K. Fecchi, I. Parolini, F. Malavasi, C. Peschle, M. Sargiacomo, U. Testa, TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway.
J. Cell Sci.
119
, 4486-4498 (2006).
[Abstract]
[Full Text]
A Cool Way to a Long Life
Authors: Kiberstis Paula A.
Published: December 2006

Caloric dietary restriction prolongs life span in a variety of organisms, and in mammals, the resultant lowering of core body temperature has been offered as one potential explanation. Conti
et al
. generated transgenic mice that overexpress mitochondrial uncoupling protein 2 in hypocretin-producing neurons within the hypothalamus, which lowers core body temperature by about 0.5ºC. In the absence of caloric restriction, the median life span of these "cool mice" was about 15% greater than that of their wild-type littermates.

B. Conti, M. Sanchez-Alavez, R. Winsky-Sommerer, M. C. Morale, J. Lucero, S. Brownell, V. Fabre, S. Huitron-Resendiz, S. Henriksen, E. P. Zorrilla, L. de Lecea, T. Bartfai, Transgenic mice with a reduced core body temperature have an increased life span.
Science
314
, 825-828 (2006).
[Abstract]
[Full Text]

C. B. Saper, Life, the universe, and body temperature.
Science
314
, 773-774 (2006).
[Abstract]
[Full Text]
Deciphering the Underlying Mechanism of Specification and Differentiation: The Sea Urchin Gene Regulatory Network
Authors: Ben-Tabou de-Leon Smadar , Davidson Eric H.
Published: December 2006

The regulatory genome functions as a vast information processor through development. It processes the initial conditions that are set by asymmetric distributions of cellular components in the egg and translates them into the onset of spatially localized specification states. It regulates the timely differential activation of signaling molecules and transcription factors that divide the emerging domains into subdomains. It also governs the activation of groups of differentiation genes, the genes that encode, at the protein level, the functional and the structural properties of a cell type. The sea urchin endomesoderm gene regulatory network provides a window into the different levels of the regulatory apparatus. It demonstrates how the static physical genomic components define functional connections between the various regulatory genes that act together to conduct the dynamical developmental program.