bluuebunny/crossref_metadata_2025 huggingface dataset:
Nicotine and Synaptic Plasticity in Prefrontal Cortex
Authors: McGehee Daniel S.
Published: September 2007

Nicotinic receptor activation enhances working memory and attention. The prefrontal cortex is a key brain area involved in working memory, and plasticity of excitatory synaptic transmission within the cortex is likely an important cellular mechanism of memory. A recent study has explored the cellular and synaptic basis of nicotine’s effects on excitability within the prefrontal cortex. The findings suggest that nicotine enhances inhibitory synaptic inputs to layer V pyramidal cells, which suppresses induction of long-term potentiation (LTP). This inhibitory effect can be overcome by stimulating the pyramidal cells in bursts, which suggests a modification in the signal-to-noise ratio for synaptic input. Thus, the impact of strong stimuli on working memory would be enhanced when combined with nicotinic receptor activity. These findings may lead to novel and more effective treatments for memory disorders.
Feeling the Itch
Authors: Adler Elizabeth M.
Published: September 2007

The disagreeable nature of itching--defined as far back as the 17th century as an unpleasant skin sensation that elicits the urge to scratch--is apparent to anyone who has wandered into a clump of poison ivy or experienced a mosquito bite. The identity of the central mediator of this "unpleasant sensation," however, has been unclear. Sun and Chen found that, in mice, a subset of unmyelinated dorsal root ganglion neurons expressed gastrin-releasing peptide (GRP) and that the GRP receptor (GRPR) was specifically localized to lamina I of the dorsal horn of the spinal cord (locations and neuron type consistent with a possible role in mediating itch perception). Mutant mice lacking the GRPR showed responses to heat and pain that were comparable to those of wild-type mice, but they displayed an attenuated scratching response to various histamine-dependent and -independent pruritogenic stimuli. Injection of a GRPR agonist into the cerebrospinal fluid of wild-type mice elicited scratching, whereas injection of a GRPR antagonist inhibited scratching in response to pruritogenic stimuli. Thus, the authors conclude that, at the level of the spinal cord, the GRPR is a mediator of an itch-specific signaling pathway--information that may provide an avenue toward the effective therapy of chronic and intractable pruritis.

Y.-G. Sun, Z.-F. Chen, A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
Nature
448
, 700-703 (2007).
[PubMed]
Hyperactive Antimicrobial Response Produces Rosacea
Authors: Gough Nancy R.
Published: September 2007

Rosacea is a painful acne-like skin disorder, characterized by dilated blood vessels causing persistent redness (or erythema), that affects people over the age of 30. Yamasaki
et al
. provide evidence that the antimicrobial cathelicidin peptides, which are chemotactic, angiogenic, and bactericidal and are important for innate immune responses in the skin, are implicated in the pathogenesis of rosacea. Skin biopsies of patients with rosacea and normal controls were compared, and the rosacea samples had elevated cathelicidin based on immunostaining and analysis of cathelicidin mRNA. In addition, the processed and active form was more abundant in the rosacea samples. Processing involves cleavage of the proprotein near the C terminus, which in human skin is done by the kallikrein family protease stratum corneum tryptic enzyme (SCTE). Rosacea samples had elevated abundance of SCTE compared with normal skin samples, and protease activity was also elevated based on in situ zymography. To ascertain whether the elevated active cathelicidin peptides could contribute to the rosacea symptoms, the most abundant peptides, LL-37 and FA-29, from the rosacea samples were added to cultured human keratinocytes or injected subcutaneously into mice. These rosacea-enriched peptides stimulated interleukin-8 production from the keratinocytes and caused erythema, vascular dilation, neutrophil infiltration, thrombosis, and hemorrhage in the injected skin. Cathelicidin peptides from normal skin did not have these effects on cultured keratinocytes or mouse skin. Injection of SCTE caused similar symptoms. In mice deficient for the gene
Camp
, which encodes cathelicidin, inflammation was substantially diminished after application of a contact skin irritant or physical abrasion. In mice deficient for the gene encoding the protease inhibitor SPINK5, which inhibits SCTE, the cathelicidin peptide profile was similar to that seen in rosacea. Bevins and Liu discuss the clinical implications of these findings.

K. Yamasaki, A. Di Nardo, A. Bardan, M. Murakami, T. Ohtake, A. Coda, R. A. Dorschner, C. Bonnart, P. Descargues, A. Hovnanian, V. B. Morhenn, R. L. Gallo, Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.
Nat. Med.
13
, 975-980 (2007).
[PubMed]

C. L. Bevins, F.-T. Liu, Rosacea: Skin innate immunity gone awry?
Nat. Med.
13
, 904-906 (2007).
[PubMed]
IKKβ Promotes Tumorigenesis
Authors: Gough Nancy R.
Published: September 2007

The tuberous sclerosis complex composed of TSC1 and TSC2, both tumor suppressors, inhibits the activity of the mTOR (mammalian target of rapamycin) pathway, which controls protein synthesis, cell proliferation, and production of vascular endothelial growth factor (VEGF). Lee
et al
. report that inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β, stimulate the mTOR pathway (detected as phosphorylation of the mTOR substrate S6K) in breast cancer cell lines and untransformed mammary epithelial cells. Activation of the mTOR pathway by TNF-α was lost if activity of inhibitor of nuclear factor κB kinase β (IKKβ) was decreased pharmacologically or by transfection of a dominant-negative inhibitor, by siRNA-mediated knockdown, or in
Ikkβ
knockout cells. IKKβ was not required for stimulation of mTOR signaling by growth factors or mitogens. IKKβ directly interacted with TSC1 and phosphorylated TSC1 on Ser
487
and Ser
511
both in vitro and in vivo. In cells expressing a mutant TSC1 [TSC1(SSAA)] in which the two serines were replaced with alanines, TNF-α failed to stimulate mTOR activity. Coimmunoprecipitation experiments with cells exposed to TNF-α suggested that phosphorylation by IKKβ disrupted the formation of the TSC1 and TSC2 complex, which is required for this complex to inhibit mTOR activity. In vivo tumorigenesis assays using TSC1 or TSC1(SSAA) or a phosphorylation mimic mutant [TSC1(SSDD)] showed that only wild-type TSC1 and TSC1(SSAA) had tumor-suppressing effects and that the blood vessel density of tumors with TSC1(SSDD) was higher than in the tumors with wild-type or TSC1(SSAA). Wild-type and TSC1(SSAA), but not TSC1(SSDD), exhibited the antiangiogenic effect of decreasing VEGF secretion when transfected into cultured cells. Thus, IKKβ-mediated inactivation of TSC1 may be one mechanism by which inflammation contributes to cancer progression. Phosphorylation of TSC1 at Ser
511
correlated with breast cancer tumors that were also high in phosphorylated (and active) IKKβ and high in TNF-α. Additionally, breast tumor samples with high phosphorylated TSC1 (Ser
511
) and high phosphorylated S6K were associated with poor survival. Thus, this inflammatory connection appears to be an important aspect to cancer prognosis.

D.-F. Lee, H.-P. Kuo, C.-T. Chen, J.-M. Hsu, C.-K. Chou, Y. Wei, H.-L. Sun, L.-Y. Li, B. Ping, W.-C. Huang, X. He, J.-Y. Hung, C.-C. Lai, Q. Ding, J.-L. Su, J.-Y. Yang, A. A. Sahin, G. N. Hortobagyi, F.-J. Tsai, C.-H. Tsai, M.-C. Hung, IKKβ suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway.
Cell
130
, 440-455 (2007).
[Online Journal]
Calcium and Chemotaxis
Authors: Foley John F.
Published: September 2007

Chemokines are chemoattractant cytokines that act through G protein-coupled receptors (GPCRs) to mediate the directed migration (or chemotaxis) of leukocytes. Chemokine receptors couple to heterotrimeric guanine nucleotide-binding proteins (G proteins) to activate phosphoinositide 3-kinase (PI3K) and phospholipase C (PLC). PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP
2
) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP
3
), which is critical for leukocyte chemotaxis. PLC-β hydrolyzes PIP
2
to produce both inositol 1,4,5-trisphosphate (IP
3
), which stimulates intracellular Ca
2+
mobilization, and diacylglycerol (DAG), which is required for the activity of many isoforms of protein kinase C (PKC). PLC-β2 and PLC-β3 are not required for the chemotaxis of neutrophils; however, the role of these enzymes in mediating lymphocyte chemotaxis has been unclear. Bach
et al
. isolated T lymphocytes from wild-type mice and mice deficient in both PLC-β2 and PLC-β3 (PLC-β2β3 KO mice) and performed chemotaxis assays in which they determined the percentages of cells that migrated in response to the chemokine SDF-1α, the ligand for the chemokine receptor CXCR4. The percentage of responding PLC-β2β3 KO T lymphocytes was about half that of the wild-type cells, over a range of concentrations of SDF-1α. This was not due to differences in CXCR4 abundance between the PLC-β2β3 KO and wild-type T lymphocytes, as assessed by flow cytometry. Chelation of intracellular Ca
2+
largely inhibited chemotaxis of wild-type T lymphocytes to SDF-1α, whereas pharmacological inhibition of PKC had no such effect. Intracellular Ca
2+
flux assays demonstrated that SDF-1α-induced Ca
2+
mobilization was severely compromised in PLC-β2β3 KO compared with wild-type T lymphocytes. These data suggest that PLC-β-mediated intracellular Ca
2+
mobilization, but not PKC activation, is important for T lymphocyte chemotaxis. Although chemokine receptor-mediated activation of PI3K is critical for the chemotaxis of all leukocyte subsets, the contribution of PLC-β isoforms to chemotaxis appears to be cell-specific.

T. L. Bach, Q.-M. Chen, W. T. Kerr, Y. Wang, L. Lian, J. K. Choi, D. Wu, M. G. Kazanietz, G. A. Koretzky, S. Zigmond, C. S. Abrams, Phospholipase Cβ is critical for T cell chemotaxis.
J. Immunol.
179
, 2223-2227 (2007).
[PubMed]
Wnt, the Fountain of Youth?
Authors: Ray L. Bryan
Published: September 2007

Wnt proteins are secreted ligands that bind to cell surface receptors and have important effects during development, which it now seems may also contribute to phenotypes of stem and progenitor cells associated with aging. Liu
et al
. examined stem cell properties in mice carrying a mutation in the Klotho protein, which show characteristics of accelerated aging. They observed increased senescence of stem cells in the mutant mice and found that the Klotho protein physically interacted with and inhibited Wnt proteins in transfected cells. Exposure of mouse embryo fibroblasts in culture to excessive Wnt signaling enhanced senescence, and in transgenic mice it also promoted senescence of skin cells. Brack
et al
. found that Wnt signaling appeared to be more active in aging animals. Injection of Wnt3A into young regenerating muscle reduced proliferation and increased deposition of connective tissue. Thus, antagonizing Wnt signals could provide a strategy to ease the effects of aging and age-related diseases.

H. Liu, M. M. Fergusson, R. M. Castilho, J. Liu, L. Cao, J. Chen, D. Malide, I. I. Rovira, D. Schimel, C. J. Kuo, J. S. Gutkind, P. M. Hwang, T. Finkel, Augmented Wnt signaling in a mammalian model of accelerated aging.
Science
317
, 803-806 (2007).
[Abstract]
[Full Text]

A. S. Brack, M. J. Conboy, S. Roy, M. Lee, C. J. Kuo, C. Keller, T. A. Rando, Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis.
Science
317
, 807-810 (2007).
[Abstract]
[Full Text]
Focus Issue: Cells on the Move
Authors: Foley John F. , Gough Nancy R.
Published: September 2007

Science
's STKE explores the molecular mechanisms that allow cells to navigate and migrate in a particular direction. New models for forming cellular extensions called filopodia that initiate migration, along with methods for analysis of the proteomic differences between the cell body and cellular protrusions (pseudopodia), are highlighted. The processes by which groups of cells, as well as individual cells, navigate in a particular direction are also featured.
Filopodia: The Fingers That Do the Walking
Authors: Gupton Stephanie L. , Gertler Frank B.
Published: September 2007

Filopodia are actin-based structures composed of parallel bundles of actin filaments and various actin-associated proteins, and they play important roles in cell-cell signaling, guidance toward chemoattractants, and adhesion to the extracellular matrix. Two mechanisms for the formation of filopodia have been suggested, each using different sets of actin-regulating proteins, creating some controversy in the field. New molecules, some of unknown functions, have also been implicated in filopodium formation, suggesting that other possible mechanisms of filopodium formation exist. We discuss established and novel proteins that mediate the formation and dynamics of filopodia, different mechanisms of filopodium formation, and the various functions that distinct filopodia perform.
Chillin’ Channels Through Internalization
Authors: Ray L. Bryan
Published: September 2007

Voltage-gated calcium channels, and L-type calcium channels (LTCs) in particular, provide a key mechanism by which electrical depolarization of a neuron is translated into changes in biochemical signaling systems that alter cellular function and gene expression. Green
et al.
show that, beyond the acute Ca
2+
-dependent inhibition of LTC conductance by calmodulin, there is an additional mechanism providing a longer-term negative feedback--Ca
2+
-dependent internalization of the channel. The authors modified the LTC Ca
v
1.2 with tags in an extracellular loop and on the intracellular N terminus, which allowed them to monitor the fraction of the channel protein that was present on the surface of individual cultured cortical neurons. Electrical depolarization of the neurons decreased the fraction of the channels that was present on the cell surface. Total internal reflection microscopy showed that the channels became internalized in endosomal vesicles. The authors identified a fragment of the channel that produced a dominant-negative inhibition of internalization and, assuming it might be sequestering a protein that regulated the channel, used it in a two-hybrid screen to find an unexpected interacting protein, eIF3e. The eIF3e protein gets its name from its association with the elongation initiation complex, but it also interacts with the proteasome and the COP9 signalosome, complexes that function to degrade or regulate proteins modified by ubiquitination. At least when overexpressed, eIF3e interacted with Ca
v
1.2 in cells, and increased amounts of eIF3e were associated with immunoprecipitated Ca
v
1.2 when cells had been depolarized. In commentary on the paper, Varela and Zamponi note that a C-terminal fragment of Ca
v
1.2 is reported to move to the nucleus and function as a transcription factor. Might eIF3e help route the channel to a compartment where proteolytic release of the C terminus would be activated for control of gene expression? Even if this intriguing scenario does not pan out, it seems likely that alterations in the density of LTCs at the cell surface is a mechanism that will affect a range of physiological processes, from cardiac function to neuronal plasticity.

E. M. Green, C. F. Barrett, G. Bultynck, S. M. Shamah, R. E. Dolmetsch, The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel Ca
v
1.2.
Neuron
55
, 615-632 (2007).
[Online Journal]

D. Varela, G. W. Zamponi, Use ‘em and lose ‘em--Activity-induced removal of calcium channels from the plasma membrane.
Neuron
55
, 539-541 (2007).
[Online Journal]
Osteocytes Losing Their Grip?
Authors: Adler Elizabeth M.
Published: September 2007

Glucocorticoid hormones, which are produced in response to stress, exhibit immunosuppressive and anti-inflammatory activity, properties that lead to their use in treating various medical conditions. Long-term use of glucocorticoids, however, leads to increased bone fragility, an undesirable side effect associated with an increase in osteocyte apoptosis. Plotkin
et al
. found that dexamethasone treatment of cultured osteocytic MLO-Y4 cells elicited apoptosis even in the presence of inhibitors of protein or RNA synthesis but failed to do so in the presence of the glucocorticoid receptor antagonist RU486. Dexamethasone also stimulated an RU486-sensitive decrease in the number of cytoplasmic processes (an indicator of cell detachment), as well as cytoskeletal reorganization, both of which occurred substantially before apoptosis. In contrast, apoptosis in response to etoposide was not preceded by cell detachment. A cell-permeable caspase inhibitor prevented apoptosis, but not dexamethasone-mediated cell detachment. Cells overexpressing focal adhesion kinase (FAK) are resistant to dexamethasone-induced apoptosis. In contrast, expression of an inactive mutant form of Pyk2--a FAK-related kinase that was rapidly phosphorylated on tyrosine 402 in response to dexamethasone--or a form that could not be phosphorylated on tyrosine 402 (Y402F Pyk2) prevented dexamethasone-mediated apoptosis. Furthermore, Pyk2 knockdown rendered cells resistant to both dexamethasone-mediated detachment and apoptosis. c-Jun N-terminal kinase (JNK) is a target of Pyk2, and both pharmacological inhibition of JNK and expression of a dominant-negative JNK mutant inhibited dexamethasone-dependent cell detachment and apoptosis. Moreover, JNK overexpression (or overexpression of an upstream JNK activator) counteracted the antiapoptotic effects of Y402F Pyk2. Thus, the authors conclude that glucocorticoids elicit osteocyte apoptosis by inhibiting cell adhesion through a pathway involving Pyk2 and JNK.

L. I. Plotkin, S. C. Manolagas, T. Bellido, Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival: Evidence for inside-out signaling leading to anoikis.
J. Biol. Chem.
282
, 24120-24130 (2007).
[Abstract]
[Full Text]
Hold Them Back
Authors: Foley John F.
Published: September 2007

Brassinosteroids (BRs) are plant steroids. They bind to and activate the cell-surface receptor kinase BRI1, which initiates a cascade of responses that regulate the phosphorylation states of the transcription factors BZR1 and BZR2. Phosphorylation of BZRs renders them inactive, whereas dephosphorylation results in their activation. Gampala
et al
. investigated the mechanisms by which BR-mediated modulation of BZR1 phosphorylation affected its activity. They expressed a fusion protein of BZR1 and yellow fluorescent protein (YFP) in transgenic
Arabidopsis
and used confocal microscopy to show that treatment of seedlings with brassinolide (BL), a potent BR, resulted in the nuclear accumulation of BZR1-YFP. Subcellular fractionation and Western blotting demonstrated that nonphosphorylated BZR1 was enriched in the nucleus, whereas phosphorylated BZR1 was enriched in the cytosol. Radiolabeled DNA hybridized to nonphosphorylated but not phosphorylated recombinant BZR1 on a blot. A yeast two-hybrid screen identified two isoforms of 14-3-3 proteins as binding partners for BZR1. The 14-3-3 proteins bind to targets in a sequence- and phosphorylation-dependent manner and regulate many cellular processes, often by protein translocation (see commentary by de Vries). Recombinant 14-3-3λ bound to phosphorylated but not nonphosphorylated BZR1 protein on a blot. Transgenic
Arabidopsis
expressing BZR1Δ (which cannot bind 14-3-3) exhibited a phenotype consistent with constitutive activation of BZR1. BZR1Δ-YFP showed increased nuclear localization compared with that of BZR1-YFP. Treatment of
Arabidopsis
with an inhibitor of 14-3-3 target protein interactions increased the nuclear accumulation of BZR1. Similar results were found for BZR2. Together, these data establish 14-3-3 proteins as important negative regulators of BR signaling.

S. S. Gampala, T.-W. Kim, J.-X. He, W. Tang, Z. Deng, M.-Y. Bai, S. Guan, S. Lalonde, Y. Sun, J. M. Gendron, H. Chen, N. Shibagaki, R. J. Ferl, D. Ehrhardt, K. Chong, A. L. Burlingame, Z.-Y. Wang, An essential role for 14-3-3 proteins in brassinosteroid signal transduction in
Arabidopsis
.
Dev. Cell
13
, 177-189 (2007).
[PubMed]

S. C. de Vries, 14-3-3 proteins in plant brassinosteroid signaling.
Dev. Cell
13
, 162-164 (2007).
[PubMed]
Understanding Selective Synapse Elimination
Authors: Hurtley Stella M.
Published: September 2007

Synapse elimination is a hallmark of neural circuit maturation during development. Many synapses are eliminated after an initial phase of synapse formation. However, little is known about the molecular machinery that executes synaptic elimination or why certain synapses are selectively eliminated while other synapses persist and grow. Ding
et al
. (see the Perspective by Miller) examined synapse elimination in the nematode worm and found that a ubiquitin E3 ligase complex plays a key role. The activity of the ubiquitin-proteasome system was tightly regulated by a synaptic adhesion molecule, which protected certain synapses from selective elimination.

M. Ding, D. Chao, G. Wang, K. Shen, Spatial regulation of an E3 ubiquitin ligase directs selective synapse elimination.
Science
317
, 947-951 (2007).
[Abstract]
[Full Text]

D. M. Miller, Synapses here and not everywhere.
Science
317
, 907-908 (2007).
[Summary]
[Full Text]
The Functions of Plant TIR Domains
Authors: Burch-Smith Tessa M. , Dinesh-Kumar Savithramma P.
Published: September 2007

The Toll-interleukin-1 receptor (TIR) domain is found in innate immune molecules of insects, animals, and plants. There is a marked conservation of the signaling pathways used by TIR domain–containing immune receptors in animals. In plants, pathways involving TIR domain–containing proteins are not as well understood, but data are beginning to suggest important differences between the functions of plant and animal proteins. Plant Resistance proteins use their TIR domains for pathogen detection, and they may also function in the nucleus to direct the expression of genes involved in defense responses. This shows that plants have used their TIR domains to perform a multitude of duties and have expanded the functions of the TIR domain beyond those seen in animals.
Structure and Function of the PB1 Domain, a Protein Interaction Module Conserved in Animals, Fungi, Amoebas, and Plants
Authors: Sumimoto Hideki , Kamakura Sachiko , Ito Takashi
Published: September 2007

Proteins containing the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants, participate in diverse biological processes. The PB1 domains adopt a ubiquitin-like β-grasp fold, containing two α helices and a mixed five-stranded β sheet, and are classified into groups harboring an acidic OPCA motif (type I), the invariant lysine residue on the first β strand (type II), or both (type I/II). The OPCA motif of a type I PB1 domain forms salt bridges with basic residues, especially the conserved lysine, of a type II PB1 domain, thereby mediating a specific PB1-PB1 heterodimerization, whereas additional contacts contribute to high affinity and specificity of the modular interaction. The canonical PB1 dimerization is required for the formation of complexes between p40
phox
and p67
phox
(for activation of the NADPH oxidase crucial for mammalian host defense), between the scaffold Bem1 and the guanine nucleotide exchange factor Cdc24 (for polarity establishment in yeasts), and between the polarity protein Par6 and atypical protein kinase C (for cell polarization in animal cells), as well as for the interaction between the mitogen-activated protein kinase kinase kinases MEKK2 or MEKK3 and the downstream target mitogen-activated protein kinase kinase MEK5 (for early cardiovascular development in mammals). PB1 domains can also mediate interactions with other protein domains. For example, an intramolecular interaction between the PB1 and PX domains of p40
phox
regulates phagosomal targeting of the microbicidal NADPH oxidase; the PB1 domain of MEK5 is likely responsible for binding to the downstream kinase ERK5, which lacks a PB1 domain; and the scaffold protein Nbr1 associates through a PB1-containing region with titin, a sarcomere protein without a PB1 domain. This Review describes various aspects of PB1 domains at the molecular and cellular levels.
Helping p53 Choose a Target Gene
Authors: Gough Nancy R.
Published: September 2007

The tumor suppressor p53 controls the cellular response to genotoxic stress by promoting either cell cycle arrest or apoptosis, depending on the amount of damage (see Aylon and Oren for summary of p53 functions and regulatory mechanisms). Much of the function of p53 in this cell choice of life or death is related to which genes it targets: Do those genes encode proapoptotic proteins or are encoded proteins involved in mediating cell cycle arrest? Two articles this week identify two new participants in controlling p53 target gene selection. Das
et al
. identified hematopoietic zinc finger (Hzf), which is itself encoded by a p53-regulated gene, as a protein that directly interacted with p53 and promoted the activation of cell cycle arrest genes, while inhibiting the expression of proapoptotic genes, in response to mild DNA damage. This function was determined using RNA interference assays and mouse embryo fibroblasts deficient in Hzf. Initially, in response to mild genotoxic stress, Hzf abundance increased; however, after prolonged exposure of cells to etopside or extended forced expression of p53, Hzf abundance decreased, which was prevented by pharmacological inhibition of the proteasome. This decrease correlated with the time in which the cells begin to undergo apoptosis; thus, Hzf appears to be one p53 target and partner that contributes to the choice of cell cycle arrest. In a related article, Tanaka
et al
. found that human cellular apoptosis susceptibility protein (hCAS, which is the homolog of the yeast protein CSE1) bound to a subset of p53-containing chromatin complexes, although binding of hCAS and p53 were independent of each other. When hCAS was depleted by RNA interference methods, the p53 target genes with which hCAS was normally associated showed decreased p53-dependent expression. Although hCAS-targeted genes did not fall exclusively into the cell cycle or apoptosis categories, hCAS does appear to be another mechanism by which p53 target gene selection is made.

Y. Aylon, M. Oren, Living with p52, Dying of p53.
Cell
130
, 597-600 (2007).
[PubMed]

S. Das, L. Raj, B. Zhao, Y. Kimura, A. Bernstein, S. A. Aaronson, S. W. Lee, Hzf determines cell survival upon genotoxic stress by modulating p53 transactivation.
Cell
130
, 624-637 (2007).
[PubMed]

T. Tanaka, S. Ohkubo, I. Tatsuno, C. Prives, hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes.
Cell
130
, 638-650 (2007).
[PubMed]
Playing on Both Sides of the Field
Authors: Foley John F.
Published: September 2007

Signals from the T cell receptor (TCR) are important for activation, differentiation, and proliferation. Members of the B cell leukemia/lymphoma-2 (Bcl-2) family of proteins are critical regulators of T cell apoptosis. The proapoptotic members Bax (Bcl-2-associated X protein) and Bak (Bcl-2-antagonist/killer) prevent the accumulation of excess lymphocytes. Jones
et al
. investigated other roles for Bax and Bak in T cell physiology. The authors reconstituted irradiated recombination-activating gene-1 (RAG-1)-deficient mice, which are deficient in T cells, with bone marrow cells from
Bax
–/–
,
Bak
–/–
(DKO), or wild-type mice. TCR stimulation of DKO cells isolated from these chimeric mice resulted in defective activation and proliferation, as measured by flow cytometry and
3
[H]-thymidine incorporation. Whereas TCR stimulation of DKO cells resulted in decreased concentration of intracellular Ca
2+
([Ca
2+
]
i
) compared with that in wild-type cells, Western blotting analysis showed that phosphorylation of phospholipase Cγ isoforms, which are downstream of TCR activation, was comparable in both cell types. Treatment of DKO CD4
+
T cells with a cell-permeable inositol 1,4,5-trisphosphate (IP
3
)-ester induced lower [Ca
2+
]
i
than did treatment of wild-type cells, indicating that DKO cells have defective IP
3
-dependent Ca
2+
release from endoplasmic reticulum (ER) stores. This defect was reversed by either retroviral-mediated expression of Bax or treatment of DKO cells with ionomycin, which allows influx of extracellular Ca
2+
. DKO T cells were also defective for TCR-stimulated production of reactive oxygen species compared with wild-type cells. Together, these data establish Bax and Bak as important regulators of T cell proliferation through controlling TCR-stimulated Ca
2+
mobilization from the ER.

R. G. Jones, T. Bui, C. White, M. Madesh, C. M. Krawczyk, T. Lindsten, B. J. Hawkins, S. Kubek, K. A. Frauwirth, Y. L. Wang, S. J. Conway, H. L. Roderick, M. D. Bootman, H. Shen, J. K. Foskett, C. B. Thompson, The proapoptotic factors Bax and Bak regulate T cell proliferation through control of endoplasmic reticulum Ca
2+
homeostasis.
Immunity
27
, 268-280 (2007).
[PubMed]
Optineurin Competes with NEMO
Authors: Gough Nancy R.
Published: September 2007

Optineurin is a protein with sequence similarity to NEMO [nuclear factor-κB (NF-κB) essential modulator]. Thus, Zhu
et al
. explored whether optineurin also participates in NF-κB signaling. NEMO is part of a kinase complex that is required for activation of NF-κB and recognizes proteins that become polyubiquitinated [including those with the lysine 63 (K63) linkage] during NF-κB activation. Surprisingly, Zhu
et al
. found that cells overexpressing optineurin exhibited diminished NF-κB reporter gene expression triggered by overexpression of the upstream constituents TRAF2 (a ubiquitin ligase) or RIP (receptor interacting protein) in the NF-κB signaling pathway or by treatment of the cells with tumor necrosis factor α (TNF-α). In addition, increasing expression of optineurin decreased the coimmunoprecipitation of NEMO and polyubiquitinated RIP in TNF-α-treated cells. Both NEMO and optineurin bound to beads coated with glutathione-
S
-transferase (GST)-ubiquitin fusion protein; however optineurin showed increased binding compared with NEMO to beads with the K63-linked ubiquitin. GST-NEMO and GST-optineurin both associated with polyubiquitinated RIP, and both NEMO and optineurin coimmunoprecipitated ubiquitinated RIP from TNF-α-treated cells. However, NEMO and optineurin were never coimmunoprecipitated, suggesting an exclusive interaction with target proteins. Indeed, increasing concentrations of optineurin reduced the interaction between polyubiquitinated RIP and GST-NEMO. RNA interference studies showed that when optineurin was depleted, the activation of an endogenous NF-κB target gene, as well as a reporter gene, in response to TNF-α was increased. Thus, optineurin appears to serve as a negative regulator of NF-κB signaling by competing with NEMO for K63-linked polyubiquitinated proteins important for connecting activated receptors to NF-κB activation.

G. Zhu, C.-J. Wu, Y. Zhao, J. D. Ashwell, Optineurin negatively regulates TNFα-induced NF-κB activation by competing with NEMO for ubiquitinated RIP.
Current Biol.
17
, 1438-1443 (2007).
[PubMed]
Is Wnt a Synaptomorphogen?
Authors: Gough Nancy R.
Published: September 2007

Wnts, which are a class of ligands, are involved in many cellular processes and have been previously implicated as prosynaptogenic factors. Klassen and Shen show that the formation of synapses by the motor neuron DA9 is inhibited by a Wnt signaling pathway in
Caenorhabditis elegans
involving the Wnts LIN-44 and EGL-20, the Wnt receptor LIN-17, and the intracellular signaling component DSH-1. The pathway appeared to be a noncanonical one, as mutations in genes encoding participants in the Wnt-β-catenin pathway, the planar cell polarity pathway, and the Wnt-calcium signaling pathway did not cause the formation of synapses in regions that were asynaptic in wild-type worms. As discussed by Davis and Ghosh, it will be interesting to determine what the mechanism of Wnt regulation of synapse formation is and whether there is a dose-dependent effect that would classify Wnt as a synaptomorphogen.

M. P. Klassen, J. Shen, Wnt signaling positions neuromuscular connectivity by inhibiting synapse formation in
C. elegans
.
Cell
130
, 704-716 (2007).
[PubMed]

E. Davis, A. Ghosh, Should I stay or should I go: Wnt signals at the synapse.
Cell
130
, 593-596 (2007).
[PubMed]
Astrocytes at Single Synapses
Authors: Stern Peter
Published: September 2007

Astrocytes respond to synaptic activity and can release different gliotransmitters, which modulate neuronal activity and neurotransmission. Perea and Araque examined the role of astrocytes on synaptic transmission at single hippocampal excitatory synapses. Ca
2+
elevation in astrocytes led to a transient release of the neurotransmitter glutamate from astrocytes, which was mediated by metabotropic glutamate receptors. Potentiation became long-lasting when glial activation was paired with postsynaptic depolarization.

G. Perea, A. Araque, Astrocytes potentiate transmitter release at single hippocampal synapses.
Science
317
, 1083-1086 (2007).
[Abstract]
[Full Text]
Bacteria Seeing Blue
Authors: Ash Caroline
Published: September 2007

Phototropins, blue-light receptors in plants, are light-activated serine/threonine kinases with a flavoprotein LOV domain as their light-sensing module. In addition to the phototropins found in eukaryotes, gene-sequence analysis predicts that LOV domains should be present in prokaryotes and archaea. Swartz
et al
. (see the Perspective by Kennis and Crosson) show that a subset of genes in prokaryotes encodes for proteins that function as light-activated LOV-histidine kinases. Light activation of the LOV domain leads to the formation of a flavin-cysteinyl adduct, which is the photoreceptor-signaling state that activates the kinase domain. Light-activated LOV-histidine kinases were found in two important plant and animal pathogens and in a marine photosynthetic bacterium and indicate that the LOV-histidine kinases are an important family of bacterial photosensory receptors.

T. E. Swartz, T.-S. Tseng, M. A. Frederickson, G. Paris, D. J. Comerci, G. Rajashekara, J.-G. Kim, M. B. Mudgett, G. A. Splitter, R. A. Ugalde, F. A. Goldbaum, W. R. Briggs, R. A. Bogomolni, Blue-light-activated histidine kinases: Two-component sensors in bacteria.
Science
317
, 1090-1093 (2007).
[Abstract]
[Full Text]

J. T. M. Kennis, S. Crosson, A bacterial pathogen sees the light.
Science
317
, 1041-1042 (2007).
[Summary]
[Full Text]
Let's Get Together
Authors: Vinson Valda J.
Published: September 2007

Proteins in the eukaryotic plasma membrane mediate many different functions and are largely partitioned into clusters. Using the SNARE protein syntaxin 1 as an example, Sieber
et al
. (see the Perspective by White) investigate the mechanism of clustering using high-resolution optical imaging, quantitative biochemistry, and molecular dynamics simulations. Weak protein-protein interactions are balanced by steric repulsion to give densely crowded clusters containing about 75 syntaxins. Proteins within the cluster are immobile but can exchange with freely diffusing molecules. This conceptual framework likely applies to many other membrane proteins.

J. J. Sieber, K. I. Willig, C. Kutzner, C. Gerding-Reimers, B. Harke, G. Donnert, B. Rammner, C. Eggeling, S. W. Hell, H. Grubmüller, T. Lang, Anatomy and dynamics of a supramolecular membrane protein cluster.
Science
317
, 1072-1076 (2007).
[Abstract]
[Full Text]

S. H. White, Crowds of syntaxins.
Science
317
, 1045-1046 (2007).
[Summary]
[Full Text]
T Cell Activation by TLRs: A Role for TLRs in the Adaptive Immune Response
Authors: MacLeod Heather , Wetzler Lee M.
Published: September 2007

Toll-like receptor (TLR) activation is primarily thought to affect antigen-presenting cells (APCs) by inducing an innate immune response that can subsequently activate the adaptive immune system. However, there are increasing data that demonstrate expression and activation of TLRs on T cells, thus providing evidence for a direct role for TLRs in the activation of an adaptive immune response. A study recently demonstrated that Pam3CSK {
N
-palmitoyl-
S
-[2,3-bis(palmitoloxy)-(2
RS
)-propyl]-Cys-Ser-Lys
4
}, a TLR2 agonist lipopeptide, activates T helper 1 (T
H
1) cells and induces interferon-γ (IFN-γ) production, even in the absence of TLR1, which differs from its mechanism of activation of APCs. Moreover, whereas Pam3CSK-stimulated IFN-γ production by T
H
1 cells is ablated in the absence of both myeloid differentiation marker 88 (MyD88), an adaptor protein in the TLR pathway, and interleukin-1 receptor (IL-1R)–associated kinase–4 (IRAK4), the mitogen-activated protein kinases p38 and c-Jun N-terminal kinase (JNK) are still phosphorylated. These data suggest that TLR2 activation of T
H
1 cells occurs through a mechanism different from that described for APCs and provides further evidence of direct TLR activation of the adaptive immune system.
Intricacies of Cell Contacts
Authors: Vinson Valda J.
Published: September 2007

Cell-cell contacts in multicellular organisms are intricately regulated, and their stability is partly controlled by protein kinases and phosphatases that tune the level of tyrosine phosphorylation. Type II B receptor protein tyrosine phosphatases (RPTPs) have both adhesive and catalytic properties. Aricescu
et al
. determined the crystal structure of the full-length extracellular region of an RPTP, which forms a homophilic trans dimer that is rigid and has dimensions that match the intercellular distance at cadherin-mediated junctions. The trans interaction may act as a spacer clamp that localizes phosphatase activity near its target substrates.

A. R. Aricescu, C. Siebold, K. Choudhuri, V. T. Chang, W. Lu, S. J. Davis, P. A. van der Merwe, E. Y. Jones, Structure of a tyrosine phosphatase adhesive interaction reveals a spacer-clamp mechanism.
Science
317
, 1217-1220 (2007).
[Abstract]
[Full Text]
A Faster Route Up?
Authors: Adler Elizabeth M.
Published: September 2007

The selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressants. Like other antidepressant drugs in current use, however, SSRIs are effective only after weeks of administration, likely because of the time required for various pre- and postsynaptic adaptations to take place (see Duman). Lucas
et al
., a group that previously showed that enhancement of 5-HT neuron firing in rats by 5-HT
4
receptor agonists was maximal after only 3 days of treatment, investigated these agonists’ effects on several adaptations associated with chronic SSRI exposure. Three days of treatment with the 5-HT
4
receptor agonist RS 67333 desensitized presynaptic 5-HT
1A
autoreceptors (assessed by a decrease in the inhibition of the firing rate of 5-HT neurons in the dorsal raphe nucleus in response to acute administration of an SSRI). Three days of treatment with 5-HT
4
receptor agonists also increased tonic input to postsynaptic 5-HT
1A
receptors on hippocampal pyramidal cells, an effect that was abolished by pharmacological depletion of endogenous 5-HT. Moreover, 3 days of treatment with RS 67333 increased phosphorylation of hippocampal CREB (cAMP response element-binding protein) and hippocampal neurogenesis. In two rat behavioral models of antidepressant activity in which the effects of SSRIs were slow to emerge (inhibition of hyperlocomotion in response to olfactory bulbectomy and reversal of the inhibition of sucrose intake in response to chronic mild stress), the effects of RS 67333 were apparent earlier. Thus, 5-HT
4
receptor agonists may hold promise as a more rapidly acting class of antidepressants than existing antidepressant drugs.

G. Lucas, V. V. Rymar, J. Du, O. Mnie-Filali, C. Bisgaard, S. Manta, L. Lambas-Senas, O. Wiborg, N. Haddjeri, G. Piñeyro, A. F. Sadikot, G. Debonnel, Serotonin
4
(5-HT
4
) receptor agonists are putative antidepressants with a rapid onset of action.
Neuron
55
, 712-725 (2007).
[PubMed]

R. S. Duman, A silver bullet for the treatment of depression?
Neuron
55
, 679-681 (2007).
[PubMed]
Hydrogen Peroxide and Blood Pressure
Authors: Ray L. Bryan
Published: September 2007

The guanosine 3′,5′-monophosphate (cGMP)-dependent protein kinase (PKG) functions in the control of blood pressure. Regulation of the enzyme can occur as a consequence of signaling by NO, which stimulates formation of cGMP. The cGMP binds to PKG and activates it, which causes vasorelaxation (reduced tension of smooth muscle in blood vessel walls). Burgoyne
et al
. (see the Perspective by Hartzell) present evidence for another mechanism of control of the activity or the Iα isoform of PKG. This isoform appears to directly sense the presence of oxidants in the cell. In the presence of H
2
O
2
, PKGIα formed disulfide-linked dimers that had increased affinity for kinase substrates and showed increased enzymatic activity. Treatment of heart tissue or aortic rings with H
2
O
2
showed that relaxation was correlated with formation of the enzyme dimer, and relaxation could be produced independently of NO-dependent changes in the concentration of cGMP. The authors propose that physiological agents that alter cellular production of H
2
O
2
may act through such a mechanism to control activity of PKG1α and thus regulate blood pressure.

J. R. Burgoyne, M. Madhani, F. Cuello, R. L. Charles, J. P. Brennan, E. Schröder, D. D. Browning, P. Eaton, Cysteine redox sensor in PKGIα enables oxidant-induced activation.
Science
317
, 1393-1397 (2007).
[Abstract]
[Full Text]

H. C. Hartzell, The stress of relaxation.
Science
317
, 1331-1332 (2007).
[Summary]
[Full Text]
Polo Playing with Numb
Authors: Adler Elizabeth M.
Published: September 2007

The asymmetric distribution of various factors during cell division is one mechanism that enables stem cells both to renew their own population and to give rise to cells that continue to differentiate. In the asymmetric division of stem cell-like neuroblasts in
Drosophila
, Numb, which inhibits self-renewal, is segregated to the cell destined to differentiate. Numb segregation depends on its interaction with Partner of Numb (Pon), which becomes asymmetrically localized during mitosis. Noting that the Pon localization domain (Pon-LD) contains a serine residue (Ser
611
) that is a potential phosphorylation site for Polo, a serine/threonine kinase involved in orchestration of the cell cycle, Wang
et al
. determined that Ser
611
could be phosphorylated by a mammalian Polo-like kinase in vitro. Western and immunohistochemical analyses of wild-type flies compared with flies with
polo
loss-of-function alleles indicated that Polo phosphorylated Ser
611
in the larval fly brain in vivo. Visualization of wild-type and phospho-mutant forms of fluorescently tagged Pon-LDs implicated Ser
611
phosphorylation in regulating Pon localization during the cell cycle. The brains of larvae with hypomorphic
polo
alleles contained increased numbers of neuroblasts 96 hours after hatching compared with those of wild-type larvae--a phenotype that was suppressed by Numb overexpression--and fewer neuronally differentiated cells. Moreover, Pon and Numb were missegregated in the brains of the
polo
mutants. Segregation of atypical protein kinase C (aPKC) was also disrupted, as was mitotic spindle orientation, whereas localization of most other asymmetrically localized proteins was not. Thus, Polo provides a link between the cell cycle and the asymmetric localization of Numb and a mechanism to inhibit neuroblast self-renewal.

H. Wang, Y. Ouyang, W. G. Somers, W. Chia, B. Lu, Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon.
Nature
449
, 96-100 (2007).
[PubMed]
Dialogue Between LKB1 and AMPK: A Hot Topic at the Cellular Pole
Authors: Forcet Christelle , Billaud Marc
Published: September 2007

Disruption of cell architecture and change of energy metabolism are two traits of malignant cells. Yet, there was scant evidence that these two cancer hallmarks involved perturbations of a common signaling pathway. Enter LKB1, a kinase that is a tumor suppressor and that is an upstream activator of the adenosine monophosphate (AMP)–activated protein kinase (AMPK), a key sensor of cellular energy status. Four studies now reveal that LKB1 signals through AMPK to facilitate the formation of tight junctions and to maintain epithelial polarity. Thus, LKB1 appears to be a novel class of tumor suppressor that acts as an energy-sensing and polarity checkpoint.
Tailor-Made Toll-Like Receptor
Authors: Simpson Stephen J.
Published: September 2007

Laboratory-based immunology has revealed much about the role of innate immune receptors from insects to mammals, but to what extent do such receptors protect humans from infections? Zhang
et al
. report a primary human immunodeficiency that points to a dedicated role for a Toll-like receptor (TLR) in protection from infection with a single specific virus, without any apparent influence on other pathogens. Herpes simplex virus (HSV) causes encephalitis in children carrying a mutant allele of TLR3, which normally regulates the antiviral interferon response to virus nucleic acid in the central nervous system and in dendritic cells of the immune system. Maintenance of TLR3 in the innate armory of humans may have been driven by viral infection. These results suggest that other similarly narrow host-pathogen interactions may have also co-evolved.

S.-Y. Zhang, E. Jouanguy, S. Ugolini, A. Smahi, G. Elain, P. Romero, D. Segal, V. Sancho-Shimizu, L. Lorenzo, A. Puel, C. Picard, A. Chapgier, S. Plancoulaine, M. Titeux, C. Cognet, H. von Bernuth, C.-L. Ku, A. Casrouge, X.-X. Zhang, L. Barreiro, J. Leonard, C. Hamilton, P. Lebon, B. Héron, L. Vallée, L. Quintana-Murci, A. Hovnanian, F. Rozenberg, E. Vivier, F. Geissmann, M. Tardieu, L. Abel, J.-L. Casanova, TLR3 deficiency in patients with herpes simplex encephalitis.
Science
317
, 1522-1527 (2007).
[Abstract]
[Full Text]