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Matsumura, Kazunori, Toshiki Yagi, and Kenji Yasuda. "2P477 Coordination of cell growth and cell cycle progression in green algae(50. Non-equilibrium and complex system,Poster Session,Abstract,Meeting Program of EABS & BSJ 2006)." Seibutsu Butsuri 46, supplement2 (2006): S415. http://dx.doi.org/10.2142/biophys.46.s415_1.
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Degenkolbe, Roland, Shigehiro Nagashima, Fadel Samatey, Hideyuki Matsunami, Katsumi Imada, and Keiichi Namba. "2P258 Purification and crystallization of the FliM-FIiN complex from Salmonella(39. Cell motility,Poster Session,Abstract,Meeting Program of EABS & BSJ 2006)." Seibutsu Butsuri 46, supplement2 (2006): S360. http://dx.doi.org/10.2142/biophys.46.s360_2.
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Spitzer, H., and S. Hochstein. "A complex-cell receptive-field model." Journal of Neurophysiology 53, no. 5 (May 1, 1985): 1266–86. http://dx.doi.org/10.1152/jn.1985.53.5.1266.
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The time course of the response of a single cortical neuron to counterphase-grating stimulation may vary as a function of stimulation parameters, as shown in the preceding paper (19). The poststimulus-time histograms of the response amplitudes against time are single or double peaked, and where double peaked, the two peaks are of equal or unequal amplitudes. Furthermore, the spatial-phase dependence of cortical complex-cell responses may be a function of spatial frequency, so that the receptive field appears to have linear spatial summation at some spatial frequencies and nonlinear spatial summation at others (19). In the first part of this paper, we analyze a model receptive field that displays this behavior, and in the second part experimental data are presented and analyzed with regard to the model. The model cortical receptive field in its simplest form contains (two rows) of geniculate X-cell-like, DOG (difference-of-Gaussians)-shaped, center-surround antagonistic, circular-input subunits. We propose nonlinear summation between these two subunits, by introducing a half-wave rectification stage before pooling. The model is tested for the responses it predicts for the application of counterphase-grating stimulation. This simple model predicts the appearance of three response forms as a function of counterphase-stimulation parameters. At periodic spatial frequencies the expected-response histogram has a single peak, whose amplitude has a sinusoidal dependence on spatial phase. At spatial frequencies halfway between these, the expected-response histogram has two equal peaks whose amplitudes have a full-wave rectified sinusoidal dependence on spatial phase. At all intermediate spatial frequencies the expected-response histogram has a "mixed" form; the histogram appears sometimes with one peak, sometimes with two equal peaks, and generally with two peaks of unequal amplitude, as a function of spatial phase. Null responses are expected to appear at specific spatial phases only for the periodic spatial frequencies that give "pure" response time courses as in paragraph 5 above, and not in the more common mixed response case of paragraph 6. The analysis procedure described in the preceding paper (19) is used, separating the odd and even Fourier components of the response histograms reflecting the receptive-field intrasubunit linear summation and intersubunit nonlinear summation, respectively. We propose that this model may be used as a working hypothesis for the analysis of these aspects of the various cortical receptive-field types. Experimental data are described and discussed in terms of the model.(ABSTRACT TRUNCATED AT 400 WORDS)
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Hase, Hidenori, Yumiko Kanno, Masaru Kojima, Kaoru Hasegawa, Daisuke Sakurai, Hidefumi Kojima, Naoyuki Tsuchiya, et al. "BAFF/BLyS can potentiate B-cell selection with the B-cell coreceptor complex." Blood 103, no. 6 (March 15, 2004): 2257–65. http://dx.doi.org/10.1182/blood-2003-08-2694.
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Abstract The tumor necrosis factor (TNF)–like ligand BAFF/BLyS (B-cell activating factor of the TNF family/B-lymphocyte stimulator) is a potent B-cell survival factor, yet its functional relationship with other B-cell surface molecules such as CD19 and CD40 is poorly understood. We found that follicular dendritic cells (FDCs) in human lymph nodes expressed BAFF abundantly. BAFF up-regulated a B cell–specific transcription factor Pax5/BSAP (Pax5/B cell–specific activator protein) activity and its target CD19, a major component of the B-cell coreceptor complex, and synergistically enhanced CD19 phosphorylation by B-cell antigen receptor (BCR). BAFF further enhanced B-cell proliferation, immunoglobulin G (IgG) production, and reactivity to CD154 by BCR/CD19 coligation and interleukin-15 (IL-15). Our results suggest that BAFF may play an important role in FDC–B-cell interactions through the B-cell coreceptor complex and a possibly sequential link between the T cell–independent and –dependent B-cell responses in the germinal centers.
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Feng, Shuju, Nicolaos Christodoulides, and Michael H. Kroll. "The Glycoprotein Ib/IX Complex Regulates Cell Proliferation." Blood 93, no. 12 (June 15, 1999): 4256–63. http://dx.doi.org/10.1182/blood.v93.12.4256.
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Abstract The glycoprotein (Gp) Ib/IX complex contains three transmembranous leucine-rich repeat polypeptides (GpIb, GpIbβ, and GpIX) that form the platelet von Willebrand factor (vWF) receptor. GpIb/IX functions to effect platelet adhesion, activation, and aggregation under conditions of high shear stress. GpIb/IX is expressed late in the ontogeny of megakaryocytes, the precursor cell that releases platelets when it reaches its terminal stage of differentiation. Because signal pathways can be reused at different stages of development by integration with different effector pathways and because cellular adhesion through other receptor families often modulates cell growth, the hypothesis that GpIb/IX regulates cell growth was investigated. The surface expression of recombinant GpIb decreases the proliferation of transduced CHO cells. GpIb causes growth arrest in the G1 phase of the cell cycle associated with the induction of the cyclin-dependent kinase inhibitor p21. G1 arrest induced by recombinant GpIb in heterologous cells requires signaling through the 14-3-3ζ binding domain of GpIb and is partially dependent on its engagement by the extracellular ligand vWF. Growth arrest induced by the expression of recombinant GpIb/IX is followed by apoptosis of the transduced cells. The endogenous expression of GpIb in human hematopoietic cells is associated with decreased proliferation. These results suggest that the expression of the GpIb/IX complex regulates megakaryocyte growth.
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Murad, Kari L., Edmund J. Gosselin, John W. Eaton, and Mark D. Scott. "Stealth Cells: Prevention of Major Histocompatibility Complex Class II-Mediated T-Cell Activation by Cell Surface Modification." Blood 94, no. 6 (September 15, 1999): 2135–41. http://dx.doi.org/10.1182/blood.v94.6.2135.
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Abstract Transfusion or transplantation of T lymphocytes into an allogeneic recipient can evoke potent immune responses including, in immunocompromised patients, graft-versus-host disease (GVHD). As our previous studies demonstrated attenuated immunorecognition of red blood cells covalently modified with methoxy(polyethylene glycol) (mPEG), we hypothesized that T-cell activation by foreign antigens might similarly be prevented by mPEG modification. Mixed lymphocyte reactions (MLR) using peripheral blood mononuclear cells (PBMC) from HLA class II disparate donors demonstrate that mPEG modification of PBMC effectively inhibits T-cell proliferation (measured by 3H-thymidine incorporation) in a dose-dependent manner. Even slight derivatization (0.4 mmol/L mPEG per 4 × 106 cells) resulted in a ≥75% decrease, while higher concentrations caused ≥96% decrease in proliferation. Loss of PBMC proliferation was not due to either mPEG-induced cytotoxicity, as viability was normal, or cellular anergy, as phytohemagglutinin (PHA)-stimulated mPEG-PBMC demonstrated normal proliferative responses. Addition of exogenous interleukin (IL)-2 also had no proliferative effect, suggesting that the mPEG-modified T cells were not antigen primed. Flow cytometric analysis demonstrates that mPEG-modification dramatically decreases antibody recognition of multiple molecules involved in essential cell:cell interactions, including both T-cell molecules (CD2, CD3, CD4, CD8, CD28, CD11a, CD62L) and antigen-presenting cell (APC) molecules (CD80, CD58, CD62L) likely preventing the initial adhesion and costimulatory events necessary for immune recognition and response.
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Wang, Xueying, Wenwen Wang, Xiwei Wang, Ming Wang, Lijuan Zhu, Fatima Garba, Chuanhai Fu, et al. "The septin complex links the catenin complex to the actin cytoskeleton for establishing epithelial cell polarity." Journal of Molecular Cell Biology 13, no. 6 (June 1, 2021): 395–408. http://dx.doi.org/10.1093/jmcb/mjab036.
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Abstract Cell polarity is essential for spatially regulating of physiological processes in metazoans by which hormonal stimulation‒secretion coupling is precisely coupled for tissue homeostasis and organ communications. However, the molecular mechanisms underlying epithelial cell polarity establishment remain elusive. Here, we show that septin cytoskeleton interacts with catenin complex to organize a functional domain to separate apical from basal membranes in polarized epithelial cells. Using polarized epithelial cell monolayer as a model system with transepithelial electrical resistance as functional readout, our studies show that septins are essential for epithelial cell polarization. Our proteomic analyses discovered a novel septin‒catenin complex during epithelial cell polarization. The functional relevance of septin‒catenin complex was then examined in three-dimensional (3D) culture in which suppression of septins resulted in deformation of apical lumen in cysts, a hallmark seen in polarity-deficient 3D cultures and animals. Mechanistically, septin cytoskeleton stabilizes the association of adherens catenin complex with actin cytoskeleton, and depletion or disruption of septin cytoskeleton liberates adherens junction and polarity complexes into the cytoplasm. Together, these findings reveal a previously unrecognized role for septin cytoskeleton in the polarization of the apical‒basal axis and lumen formation in polarized epithelial cells.
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Kamada, Yoshiaki, Ken-ichi Yoshino, Chika Kondo, Tomoko Kawamata, Noriko Oshiro, Kazuyoshi Yonezawa, and Yoshinori Ohsumi. "Tor Directly Controls the Atg1 Kinase Complex To Regulate Autophagy." Molecular and Cellular Biology 30, no. 4 (December 7, 2009): 1049–58. http://dx.doi.org/10.1128/mcb.01344-09.
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ABSTRACT Autophagy is a bulk proteolytic process that is indispensable for cell survival during starvation. Autophagy is induced by nutrient deprivation via inactivation of the rapamycin-sensitive Tor complex1 (TORC1), a protein kinase complex regulating cell growth in response to nutrient conditions. However, the mechanism by which TORC1 controls autophagy and the direct target of TORC1 activity remain unclear. Atg13 is an essential regulatory component of autophagy upstream of the Atg1 kinase complex, and here we show that yeast TORC1 directly phosphorylates Atg13 at multiple Ser residues. Additionally, expression of an unphosphorylatable Atg13 mutant bypasses the TORC1 pathway to induce autophagy through activation of Atg1 in cells growing under nutrient-rich conditions. Our findings suggest that the direct control of the Atg1 complex by TORC1 induces autophagy.
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Agarwal, Surendra Kumar, Shantanu Pande, and Bipin Chandra. "Carney Complex." World Journal of Endocrine Surgery 6, no. 1 (2014): 1–6. http://dx.doi.org/10.5005/jp-journals-10002-1138.
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ABSTRACT The complex of myxomas, spotty skin pigmentation, and endocrine over activity or Carney complex (CNC) (MIM no. 160980) is an autosomal dominant disorder that was described in 1985 by Carney. The diagnosis of CNC is made if two of the main manifestations of the syndrome are present, these need to be confirmed by histology, biochemical testing, or imaging. Alternatively, the diagnosis is made when one of the criteria is present and the patient is a carrier of a known inactivating mutation of the PRKAR1A gene. Most cases of CNC are caused by inactivating mutations in the gene encoding one of the subunits of the protein kinase A (PKA) tetrameric enzyme, namely regulatory subunit type1 alpha (PRKAR1A), located at 17q22-24. Endocrine, dermatologic, and cardiac anomalies are the main manifestations of CNC. Skin abnormalities are present in almost 77% of the CNC patients. Variety of endocrine gland tumors are observed in CNC patients, namely growth hormone secreting pituitary adenoma (acromegaly), thyroid adenomas or carcinomas, testicular tumors (large cell calcifying sertoli cell tumors), and ovarian cyst. Cardiac myxoma is the most common primary tumor affecting the heart, accounting for nearly half of cardiac neoplasms. Approximately, 30-60% of CNC patients will develop cardiac myxoma, usually at much younger ages than the sporadic tumors. A high degree of suspicion, complete evaluation, genetic counseling is important aspect of management of Carney's disease. Once confirmed, surgical removal remains the mainstay of treatment. How to cite this article Majumdar G, Agarwal SK, Pande S, Chandra B. Carney Complex. World J Endoc Surg 2014;6(1):1-6.
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Sato, Yuko T., Kenji Kawamura, Jun Oishi, Takeshi Mori, Takuro Niidome, and Yoshiki katayama. "2P589 Structure and functional regulation of DNA complex formed with Cell-Signal responsive Gene Carrier(55. Drug design and delivery,Poster Session,Abstract,Meeting Program of EABS &BSJ 2006)." Seibutsu Butsuri 46, supplement2 (2006): S443. http://dx.doi.org/10.2142/biophys.46.s443_1.
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Prozialeck, Walter C., Michael J. Fay, Peter C. Lamar, Celeste A. Pearson, Ira Sigar, and Kyle H. Ramsey. "Chlamydia trachomatis Disrupts N-Cadherin-Dependent Cell-Cell Junctions and Sequesters β-Catenin in Human Cervical Epithelial Cells." Infection and Immunity 70, no. 5 (May 2002): 2605–13. http://dx.doi.org/10.1128/iai.70.5.2605-2613.2002.
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ABSTRACT The cadherin/catenin complex serves as an important structural component of adherens junctions in epithelial cells. Under certain conditions, β-catenin can be released from this complex and interact with transcription factors in the nucleus to stimulate the expression of genes that regulate apoptosis and cell cycle control. While studying the effects of the bacterial pathogen Chlamydia trachomatis on human cervical epithelial cells in culture, we observed that C. trachomatis caused the epithelial cells to separate from each other without detaching from their growing surface. The objective of the present study was to determine if this effect might involve the disruption of the cadherin/catenin complex. Primary cultures of human cervical epithelial cells or HeLa cells were infected with C. trachomatis serovar E. Cadherin-like immunoreactive materials and β-catenin were visualized by immunofluorescence. Preliminary studies showed that N-cadherin was the primary cadherin expressed in both the primary cultures and the HeLa cells. In noninfected cells, N-cadherin and β-catenin were colocalized at the intercellular junctional complexes. By contrast, the infected cells showed a marked loss of both N-cadherin and β-catenin labeling from the junctional complexes and the concomitant appearance of intense β-catenin labeling associated with the chlamydial inclusion. The results of Western blot analyses of extracts of C. trachomatis showed no evidence of cross-reactivity with the β-catenin antibody. These results indicate that C. trachomatis causes the breakdown of the N-cadherin/β-catenin complex and that the organism can sequester β-catenin within the chlamydial inclusion. This could represent an important mechanism by which C. trachomatis alters epithelial cell function.
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Huang, Jingxiang, Christian C. Dibble, Mika Matsuzaki, and Brendan D. Manning. "The TSC1-TSC2 Complex Is Required for Proper Activation of mTOR Complex 2." Molecular and Cellular Biology 28, no. 12 (April 14, 2008): 4104–15. http://dx.doi.org/10.1128/mcb.00289-08.
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ABSTRACT The mammalian target of rapamycin (mTOR) is a protein kinase that forms two functionally distinct complexes important for nutrient and growth factor signaling. Both complexes phosphorylate a hydrophobic motif on downstream protein kinases, which contributes to the activation of these kinases. mTOR complex 1 (mTORC1) phosphorylates S6K1, while mTORC2 phosphorylates Akt. The TSC1-TSC2 complex is a critical negative regulator of mTORC1. However, how mTORC2 is regulated and whether the TSC1-TSC2 complex is involved are unknown. We find that mTORC2 isolated from a variety of cells lacking a functional TSC1-TSC2 complex is impaired in its kinase activity toward Akt. Importantly, the defect in mTORC2 activity in these cells can be separated from effects on mTORC1 signaling and known feedback mechanisms affecting insulin receptor substrate-1 and phosphatidylinositol 3-kinase. Our data also suggest that the TSC1-TSC2 complex positively regulates mTORC2 in a manner independent of its GTPase-activating protein activity toward Rheb. Finally, we find that the TSC1-TSC2 complex can physically associate with mTORC2 but not mTORC1. These data demonstrate that the TSC1-TSC2 complex inhibits mTORC1 and activates mTORC2, which through different mechanisms promotes Akt activation.
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Adam, Soheir S., Charlene Flahiff, Mary R. Abrams, Marilyn J. Telen, and Laura M. De Castro. "The Complex Relationship Between Sickle Cell Disease and Depression." Blood 114, no. 22 (November 20, 2009): 2585. http://dx.doi.org/10.1182/blood.v114.22.2585.2585.
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Abstract Abstract 2585 Poster Board II-561 A high prevalence of depression has been described in both chronic diseases and diseases associated with chronic pain. Sickle cell disease (SCD) is a congenital and lifelong complex hematological illness in which both acute and chronic pain are described as hallmarks. Depression prevalence has also been reported as high in SCD. Clinical depression may lead to decreased compliance with prescribed medical treatments, and thus deteriorating function and health status. Furthermore, depressed patients report more frequent painful episodes. Pain and depression can also both have negative effects on health-related quality of life (QoL) measures in a chronically ill population. Methods: We performed an analytic epidemiologic prospective study to determine the prevalence of depression (as measured by the Beck Depression Inventory [BDI]) in 70 adult SCD patients at baseline (no pain episodes within 30 days) who receive their SCD disease-related care primarily from our clinic. We also assessed the association between the prevalence of depression, QoL, and severity scores measuring end organ damage as previously described (Afenyi-Annan et al. 2008). To measure mental and physical QoL domains, patients were administered the SF36 QoL scale. A short computerized test, “CNS Vital Signs,” was used to assess patients' neurocognitive function. Pain diaries were used to determine the use of short-term and long-term narcotics. Results: The sample included 38 females and 32 males, ages 19 – 76 years (mean 36). Mean severity score was 1.61 (SD 1.1; range 0–4). Nineteen patients (27%) had clinical depression by BDI. Nine of them (47%) were classified as severe. The gender ratio was 2:1 F:M. Patients with depression were significantly older (mean age 39.8 vs. 35.0 yrs, p<0.05). The ratio of hemoglobin SS versus other sickle-related hemoglobinopathies was 1:1 in those with depression versus 2:1 in those without depression. Severity scores were not statistically different between those with or without depression (1.8 ±1.1 vs. 1.5±1.2). Nineteen of 51 patients (37%) without depression had a prior history of central nervous system events, while only 4 of 19 (21%) with depression did; this difference was not statistically significant. Similarly, no statistical difference in neurocognitive function was noted between patients with and without depression, when tested for the following 5 domains: memory, psychomotor speed, reaction time, complex attention, and cognitive flexibility. Both the physical and mental domains of the QoL testing showed significantly lower scores for those patients with depression when compared with those without depression (p=0.007 and p<0.0001, respectively). For the mental domain, there was also a statistically significant inverse correlation between the level of depression and domain score. Lastly, neither current therapy with long-acting narcotics or antidepressive medications showed association with the presence of depression. Summary: We conclude that there is likely a complex and thus far poorly understood interaction between multiple SCD cofactors and the presence of depression in this patient population. QoL rather than disease severity is the measure most strongly related to depression in our study. Disclosures: No relevant conflicts of interest to declare.
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Schaks, Matthias, Grégory Giannone, and Klemens Rottner. "Actin dynamics in cell migration." Essays in Biochemistry 63, no. 5 (September 24, 2019): 483–95. http://dx.doi.org/10.1042/ebc20190015.
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Abstract Cell migration is an essential process, both in unicellular organisms such as amoeba and as individual or collective motility in highly developed multicellular organisms like mammals. It is controlled by a variety of activities combining protrusive and contractile forces, normally generated by actin filaments. Here, we summarize actin filament assembly and turnover processes, and how respective biochemical activities translate into different protrusion types engaged in migration. These actin-based plasma membrane protrusions include actin-related protein 2/3 complex-dependent structures such as lamellipodia and membrane ruffles, filopodia as well as plasma membrane blebs. We also address observed antagonisms between these protrusion types, and propose a model – also inspired by previous literature – in which a complex balance between specific Rho GTPase signaling pathways dictates the protrusion mechanism employed by cells. Furthermore, we revisit published work regarding the fascinating antagonism between Rac and Rho GTPases, and how this intricate signaling network can define cell behavior and modes of migration. Finally, we discuss how the assembly of actin filament networks can feed back onto their regulators, as exemplified for the lamellipodial factor WAVE regulatory complex, tightly controlling accumulation of this complex at specific subcellular locations as well as its turnover.
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Eberharter, Anton, David E. Sterner, David Schieltz, Ahmed Hassan, John R. Yates, Shelley L. Berger, and Jerry L. Workman. "The ADA Complex Is a Distinct Histone Acetyltransferase Complex in Saccharomyces cerevisiae." Molecular and Cellular Biology 19, no. 10 (October 1, 1999): 6621–31. http://dx.doi.org/10.1128/mcb.19.10.6621.
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ABSTRACT We have identified two Gcn5-dependent histone acetyltransferase (HAT) complexes from Saccharomyces cerevisiae, the 0.8-MDa ADA complex and the 1.8-MDa SAGA complex. The SAGA (Spt-Ada-Gcn5-acetyltransferase) complex contains several subunits which also function as part of other protein complexes, including a subset of TATA box binding protein-associated factors (TAFIIs) and Tra1. These observations raise the question of whether the 0.8-MDa ADA complex is a subcomplex of SAGA or whether it is a distinct HAT complex that also shares subunits with SAGA. To address this issue, we sought to determine if the ADA complex contained subunits that are not present in the SAGA complex. In this study, we report the purification of the ADA complex over 10 chromatographic steps. By a combination of mass spectrometry analysis and immunoblotting, we demonstrate that the adapter proteins Ada2, Ada3, and Gcn5 are indeed integral components of ADA. Furthermore, we identify the product of the S. cerevisiae gene YOR023C as a novel subunit of the ADA complex and name it Ahc1 for ADA HAT complex component 1. Biochemical functions of YOR023C have not been reported. However,AHC1 in high copy numbers suppresses the cold sensitivity caused by particular mutations in HTA1 (I. Pinto and F. Winston, personal communication), which encodes histone H2A (J. N. Hirschhorn et al., Mol. Cell. Biol. 15:1999–2009, 1995). Deletion ofAHC1 disrupted the integrity of the ADA complex but did not affect SAGA or give rise to classic Ada− phenotypes. These results indicate that Gcn5, Ada2, and Ada3 function as part of a unique HAT complex (ADA) and represent shared subunits between this complex and SAGA.
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Delgoffe, Greg M., Thomas P. Kole, Yan Zheng, Bo Xiao, Paul F. Worley, Sara C. Kozma, and Jonathan Powell. "TOR Complex 1 and TOR Complex 2 Differentially Regulate Effector and Regulatory T Cell Differentiation." Blood 112, no. 11 (November 16, 2008): 675. http://dx.doi.org/10.1182/blood.v112.11.675.675.
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Abstract Effector T cell lineage commitment is determined by the integration of multiple and sometimes opposing signals. Our lab has identified mTOR, an evolutionarily conserved serine/threonine kinase, as a crucial protein dictating the outcome of T cell fate in response to antigen. To do this we utilized a Cre-lox system to conditionally delete mTOR in T cells. In such mice, although mTOR is deleted in the double-positive stage, lymphocyte populations in the spleen and the periphery are comparable to wild-type mice. T cells lacking mTOR proliferate more slowly but secrete appropriate levels of IL-2 upon initial stimulation. However, such cells fail to differentiate into Th1, Th2 or Th17 effector T cells under the appropriate skewing conditions. This failure to differentiate is the result of decreases in appropriate STAT activation and the concomitant lack of upregulation in lineage specific transcription factors. Notably, under normally activating conditions, T cells lacking mTOR preferentially differentiate into Foxp3+ regulatory cells. Supporting this observation, mTOR deficient T cells display hyperactive Smad3 activation, even in the absence of exogenous TGF-β. mTOR signals through two known signaling complexes, TORC1 and TORC2. TORC1 contains Rheb, mTOR, GβL, and raptor, while TORC2 contains mSin1, mTOR, GβL, and rictor. In order to determine the specific role of TORC1 in T cell lineage commitment we conditionally deleted Rheb in T cells. Upon activation such cells fail to phosphorylate the TORC1 substrate S6K-1 while demonstrating normal TORC2 activity. As was the case for the mTOR−/− T cells, Rheb−/− T cells fail to differentiate into Th1 and Th17 cells when skewed in vitro. However, unlike mTOR−/− T cells, the Rheb deficient T cells are capable of becoming Th2 cells. In spite of lacking TORC1 activity, T cells lacking Rheb do not spontaneously develop into Foxp3+ cells. Such observations implicate a specific and novel role for Rheb in regulating T cell lineage commitment. Overall, our data identify mTOR as a regulator of T cell lineage commitment through which TORC1 and TORC2 signaling differentially regulate T cell fate. These findings support a novel paradigm whereby T cell activation induces a default pathway of differentiation to regulatory T cells and that TORC2 signaling is required to divert differentiation to appropriately programmed effector lineages.
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Hinck, L., I. S. Näthke, J. Papkoff, and W. J. Nelson. "Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly." Journal of Cell Biology 125, no. 6 (June 15, 1994): 1327–40. http://dx.doi.org/10.1083/jcb.125.6.1327.
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Calcium-dependent cell-cell adhesion is mediated by the cadherin family of cell adhesion proteins. Transduction of cadherin adhesion into cellular reorganization is regulated by cytosolic proteins, termed alpha-, beta-, and gamma-catenin (plakoglobin), that bind to the cytoplasmic domain of cadherins and link them to the cytoskeleton. Previous studies of cadherin/catenin complex assembly and organization relied on the coimmunoprecipitation of the complex with cadherin antibodies, and were limited to the analysis of the Triton X-100 (TX-100)-soluble fraction of these proteins. These studies concluded that only one complex exists which contains cadherin and all of the catenins. We raised antibodies specific for each catenin to analyze each protein independent of its association with E-cadherin. Extracts of Madin-Darby canine kidney epithelial cells were sequentially immunoprecipitated and immunoblotted with each antibody, and the results showed that there were complexes of E-cadherin/alpha-catenin, and either beta-catenin or plakoglobin in the TX-100-soluble fraction. We analyzed the assembly of cadherin/catenin complexes in the TX-100-soluble fraction by [35S]methionine pulse-chase labeling, followed by sucrose density gradient fractionation of proteins. Immediately after synthesis, E-cadherin, beta-catenin, and plakoglobin cosedimented as complexes. alpha-Catenin was not associated with these complexes after synthesis, but a subpopulation of alpha-catenin joined the complex at a time coincident with the arrival of E-cadherin at the plasma membrane. The arrival of E-cadherin at the plasma membrane coincided with an increase in its insolubility in TX-100, but extraction of this insoluble pool with 1% SDS disrupted the cadherin/catenin complex. Therefore, to examine protein complex assembly in both the TX-100-soluble and -insoluble fractions, we used [35S]methionine labeling followed by chemical cross-linking before cell extraction. Analysis of cross-linked complexes from cells labeled to steady state indicates that, in addition to cadherin/catenin complexes, there were cadherin-independent pools of catenins present in both the TX-100-soluble and -insoluble fractions. Metabolic labeling followed by chase showed that immediately after synthesis, cadherin/beta-catenin, and cadherin/plakoglobin complexes were present in the TX-100-soluble fraction. Approximately 50% of complexes were titrated into the TX-100-insoluble fraction coincident with the arrival of the complexes at the plasma membrane and the assembly of alpha-catenin. Subsequently, > 90% of labeled cadherin, but no additional labeled catenin complexes, entered the TX-100-insoluble fraction.(ABSTRACT TRUNCATED AT 400 WORDS)
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KUTNEY, J. P. "ChemInform Abstract: Plant Cell Cultures and Synthetic Chemistry. A Potentially Powerful Route to Complex Natural Products." ChemInform 22, no. 21 (August 23, 2010): no. http://dx.doi.org/10.1002/chin.199121325.
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O'Hearn, Sean F., Catherine E. Huang, Mike Hemann, Alevtina Zhelonkina, and Barbara Sollner-Webb. "Trypanosoma brucei RNA Editing Complex." Molecular and Cellular Biology 23, no. 21 (November 1, 2003): 7909–19. http://dx.doi.org/10.1128/mcb.23.21.7909-7919.2003.
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ABSTRACT Maturation of Trypanosoma brucei mitochondrial mRNA involves massive posttranscriptional insertion and deletion of uridine residues. This RNA editing utilizes an enzymatic complex with seven major proteins, band I through band VII. We here use RNA interference (RNAi) to examine the band II and band V proteins. Band II is found essential for viability; it is needed to maintain the normal structure of the editing complex and to retain the band V ligase protein. Previously, band III was found essential for certain activities, including maintenance of the editing complex and retention of the band IV ligase protein. Thus, band II and band V form a protein pair with features analogous to the band III/band IV ligase pair. Since band V is specific for U insertion and since band IV is needed for U deletion, their parallel organization suggests that the editing complex has a pseudosymmetry. However, unlike the essential band IV ligase, RNAi to band V has only a morphological but no growth rate effect, suggesting that it is stimulatory but nonessential. Indeed, in vitro analysis of band V RNAi cell extract demonstrates that band IV can seal U insertion when band V is lacking. Thus, band IV ligase is the first activity of the basic editing complex shown able to serve in both forms of editing. Our studies also indicate that the U insertional portion may be less central in the editing complex than the corresponding U deletional portion.
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Bender, L. B., P. J. Kooh, and M. A. Muskavitch. "Complex function and expression of Delta during Drosophila oogenesis." Genetics 133, no. 4 (April 1, 1993): 967–78. http://dx.doi.org/10.1093/genetics/133.4.967.
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Abstract Delta (Dl) encodes a cell surface protein that mediates cell-cell interactions central to the specification of a variety of cell fates during embryonic and postembryonic development of Drosophila melanogaster. We find that the Delta protein is expressed intermittently in follicle cells and in germ-line cells during stages 1-10 of oogenesis. Furthermore, Delta expression during oogenesis can be correlated with a number of morphogenetic defects associated with sterility observed in Dl mutant females, including failure of stalk formation within the germarium and subsequent fusion of egg chambers, necrosis in germ-line cells, and multiphasic embryonic arrest of fertilized eggs. We have also identified a Dl mutation that leads to context-dependent defects in Dl function during oogenesis. Direct comparison of Delta protein expression with that of the Notch protein in the ovary reveals substantial, but incomplete, coincidence of expression patterns in space and time. We discuss possible roles for the Delta protein in cell-cell interactions required for cell fate specification processes during oogenesis in light of available developmental and histochemical data.
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Parra, R. Gonzalo, Nikolaos Papadopoulos, Laura Ahumada-Arranz, Jakob El Kholtei, Noah Mottelson, Yehor Horokhovsky, Barbara Treutlein, and Johannes Soeding. "Reconstructing complex lineage trees from scRNA-seq data using MERLoT." Nucleic Acids Research 47, no. 17 (August 20, 2019): 8961–74. http://dx.doi.org/10.1093/nar/gkz706.
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Abstract Advances in single-cell transcriptomics techniques are revolutionizing studies of cellular differentiation and heterogeneity. It has become possible to track the trajectory of thousands of genes across the cellular lineage trees that represent the temporal emergence of cell types during dynamic processes. However, reconstruction of cellular lineage trees with more than a few cell fates has proved challenging. We present MERLoT (https://github.com/soedinglab/merlot), a flexible and user-friendly tool to reconstruct complex lineage trees from single-cell transcriptomics data. It can impute temporal gene expression profiles along the reconstructed tree. We show MERLoT’s capabilities on various real cases and hundreds of simulated datasets.
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Agrawal, Om P., and Klaus Scheller. "Sclerotization of Insect Cuticle in a Cell-Free System." Zeitschrift für Naturforschung C 45, no. 1-2 (February 1, 1990): 129–31. http://dx.doi.org/10.1515/znc-1990-1-223.
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Abstract Incubation of deproteinized larval cuticle (chitin flakes) with purified arylphorin (calliphorin) or larval haemolymph of Calliphora vicina resulted in the formation of a chitin-protein complex. Enzymatic oxidation of N-β-alanyldopam ine (NDAB) in the presence of chitin flakes or the chitin-protein complex, resulted in various degrees of cross-linking of NBAD-quinone formed with chitin. This study confirms the involvement of arylphorin in the process of quinone tanning of insect cuticle.
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Scarr, Rebecca B., Matthew R. Smith, Margaret Beddall, and Phillip A. Sharp. "A Novel 50-Kilodalton Fragment of Host Cell Factor 1 (C1) in G0 Cells." Molecular and Cellular Biology 20, no. 10 (May 15, 2000): 3568–75. http://dx.doi.org/10.1128/mcb.20.10.3568-3575.2000.
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ABSTRACT Host cell factor 1 (HCF-1; also called C1) is a 230-kDa protein which is cleaved posttranslationally into separate but associated N- and C-terminal polypeptides. These polypeptides are components of the C1 complex, along with Oct-1 and the viral protein VP16. The C1 complex is formed when herpes simplex virus (HSV) infects a cell and is responsible for transcription of the HSV immediate-early genes. A temperature-sensitive mutation in the N-terminal kelch domain of HCF-1 reversibly arrests cells in a G0-like state when grown at the nonpermissive temperature, and the same domain interacts with VP16 in the formation of the C1 complex. The form of HCF-1 in primary G0 cells was investigated by using peripheral blood mononucleocytes and serum-arrested human primary fibroblasts. A novel 50-kDa N-terminal fragment of HCF-1 encompassing the kelch domain was identified in the cytoplasm of these cells. This fragment arises by proteolysis of the full-length HCF-1 protein and is able to associate with VP16.
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Larschan, Erica, and Fred Winston. "The Saccharomyces cerevisiae Srb8-Srb11 Complex Functions with the SAGA Complex during Gal4-Activated Transcription." Molecular and Cellular Biology 25, no. 1 (January 1, 2005): 114–23. http://dx.doi.org/10.1128/mcb.25.1.114-123.2005.
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ABSTRACT The Saccharomyces cerevisiae SAGA (Spt-Ada-Gcn5-acetyltransferase) complex functions as a coactivator during Gal4-activated transcription. A functional interaction between the SAGA component Spt3 and TATA-binding protein (TBP) is important for TBP binding at Gal4-activated promoters. To better understand the role of SAGA and other factors in Gal4-activated transcription, we selected for suppressors that bypass the requirement for SAGA. We obtained eight complementation groups and identified the genes corresponding to three of the groups as NHP10, HDA1, and SRB9. In contrast to the srb9 suppressor mutation that we identified, an srb9Δ mutation causes a strong defect in Gal4-activated transcription. Our studies have focused on this requirement for Srb9. Srb9 is part of the Srb8-Srb11 complex, associated with the Mediator coactivator. Srb8-Srb11 contains the Srb10 kinase, whose activity is important for GAL1 transcription. Our data suggest that Srb8-Srb11, including Srb10 kinase activity, is directly involved in Gal4 activation. By chromatin immunoprecipitation studies, Srb9 is present at the GAL1 promoter upon induction and facilitates the recruitment or stable association of TBP. Furthermore, the association of Srb9 with the GAL1 upstream activation sequence requires SAGA and specifically Spt3. Finally, Srb9 association also requires TBP. These results suggest that Srb8-Srb11 associates with the GAL1 promoter subsequent to SAGA binding, and that the binding of TBP and Srb8-Srb11 is interdependent.
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Stevic, Ivan, Leslie R. Berry, and Anthony Chan. "Investigation Into Mechanisms of Prothrombinase Complex Inhibition by a Covalent Antithrombin-Heparin Complex." Blood 114, no. 22 (November 20, 2009): 2136. http://dx.doi.org/10.1182/blood.v114.22.2136.2136.
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Abstract Abstract 2136 Poster Board II-113 Introduction: Formation of the prothrombinase complex results in efficient generation of thrombin (IIa) by a vast enhancement of the factor Xa (Xa) reaction with prothrombin (II). However, the integration of Xa into the complex significantly decreases its availability for inhibition by antithrombin+heparin (AT+H). Our laboratory has developed a novel anticoagulant by covalently linking antithrombin to heparin (ATH). We have shown that ATH, compared to AT+H, significantly increased the rate of inhibition of clot-bound thrombin as well as several other coagulation factors in isolation. The present study was performed to extend understanding of the anticoagulant mechanisms of ATH by determining its inhibition of Xa within the critical prothrombinase system. Methods: Pseudo first-order kinetic experiments for the inhibition of Xa in the prothrombinase complex were performed by reacting AT+H or ATH with CaCl2, phospholipid vesicles (PC/PS), factor Va (Va), II, specific IIa inhibitor Pefabloc and Xa in buffer. At specific time intervals, the reactions were neutralized with Na2EDTA, polybrene and Xa substrate (S-2222) in buffer, followed by measurement of residual enzyme activity. Second-order rate constants (k2) were calculated from semi-logarithmic plots of residual Xa activity remaining versus time. To investigate the roles of individual components of the prothrombinase complex on the anticoagulant effects of ATH, additional experiments were performed where components of the complex (II, PC/PS or Va) were removed prior to reaction with AT+H or ATH. Results: The k2value (× 108 M−1min−1) for the inhibition of Xa alone by AT+H was 1.47 ± 0.08. Incorporation of Xa into the prothrombinase complex significantly decreased this value to 0.67 ± 0.05, p<0.001. In comparison, ATH inhibited free-Xa and prothrombinase-complexed Xa at significantly faster rates than AT+H (2.83 ± 0.15 and 2.11 ± 0.38 (p<0.01), respectively). Relative to intact prothrombinase, rates for inhibition by AT+H of Xa in complexes devoid of PC/PS, Va or II significantly increased to 1.49 ± 0.08, 1.44 ± 0.08 and 1.24 ± 0.04, p<0.001, respectively. In contrast, removal of II from prothrombinase significantly decreased the k2 for Xa inhibition by ATH to 1.57 ± 0.04, p<0.05. Although removal of PC/PS from the system resulted in a higher k2 (2.79 ± 0.14, p<0.01), removal of Va resulted in no significant change (2.09 ± 0.09, p=0.79) for ATH reactions. Conclusion: Based on these results, we conclude that the prothrombinase complex hinders the inhibitory action of AT+H on Xa, whereas ATH is less affected. In fact, ATH inhibition of the prothrombinase complex was significantly higher than the inhibition rate for either free or prothrominase-bound Xa by AT+H. We speculate that, similar to inhibition of fibrin-bound thrombin, H in the non-covalent AT+H dissociate and bind to components within the prothrombinase that repel incoming AT+H and preventing Xa inhibition. These complexes cannot occur when AT is covalently linked to H, thus allowing for enhanced inhibition of prothrominase-bound Xa by ATH. Absence of II from the prothrombinase complex removes interference of AT+H reactions by any H complexes within prothrombinase, but may antagonize inhibition by the conjugate through unproductive interactions of ATH with uncovered sites close to Xa at the phospholipid surface. These findings reveal important features involved in the enhanced anticoagulant action of ATH against prothrombinase surface-bound enzymes. Disclosures: No relevant conflicts of interest to declare.
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Moens, P. B., C. Heyting, A. J. Dietrich, W. van Raamsdonk, and Q. Chen. "Synaptonemal complex antigen location and conservation." Journal of Cell Biology 105, no. 1 (July 1, 1987): 93–103. http://dx.doi.org/10.1083/jcb.105.1.93.
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The axial cores of chromosomes in the meiotic prophase nuclei of most sexually reproducing organisms play a pivotal role in the arrangement of chromatin, in the synapsis of homologous chromosomes, in the process of genetic recombination, and in the disjunction of chromosomes. We report an immunogold analysis of the axial cores and the synaptonemal complexes (SC) using two mouse monoclonal antibodies raised against isolated rat SCs. In Western blots of purified SCs, antibody II52F10 recognizes a 30- and a 33-kD peptide (Heyting, C., P. B. Moens, W. van Raamsdonk, A. J. J. Dietrich, A. C. G. Vink, and E. J. W. Redeker, 1987, Eur. J. Cell Biol., 43: 148-154). In spreads of rat spermatocyte nuclei it produces gold grains over the cores of autosomal and sex chromosomes. The cores label lightly during the chromosome pairing stage (zygotene) of early meiotic prophase and they become more intensely labeled when they are parallel aligned as the lateral elements of the SC during pachytene (55 grains/micron SC). Statistical analysis of electronically recorded gold grain positions shows that the two means of the bimodal gold grain distribution coincide with the centers of the lateral elements. At diplotene, when the cores separate, the antigen is still detected along the length of the core and the enlarged ends are heavily labeled. Shadow-cast SC preparations show that recombination nodules are not labeled. The continued presence suggests that the antigens serve a continuing function in the cores, such as chromatin binding, and/or structural integrity. Antibody III15B8, which does not recognize the 30- and 33-kD peptides, produces gold grains predominantly between the lateral elements. The grain distribution is bimodal with the mean of each peak just inside the pairing face of the lateral element. The antigen is present where and while the cores of the homologous chromosomes are paired. From the location and the timing, it is assumed that the antigen recognized by III15B8 functions in chromosome pairing at meiotic prophase. The two anti-rat SC antibodies label rat and mouse SCs but not rabbit or dog SCs. A positive control using human CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) anti-centromere serum gives equivalent labeling of SC centromeres in the rat, mouse, rabbit, and dog. It is concluded that the SC antigens recognized by II52F10 and III15B8 are not widely conserved. The two antibodies do not bind to cellular or nuclear components of somatic cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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Flynn, Catherine M., and Dan S. Kaufman. "Donor cell leukemia: insight into cancer stem cells and the stem cell niche." Blood 109, no. 7 (November 28, 2006): 2688–92. http://dx.doi.org/10.1182/blood-2006-07-021980.
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Abstract Donor cell leukemia (DCL) is a rare complication of hematopoietic cell transplantation (HCT). Its incidence has been reported between 0.12% and 5%, although the majority of cases are anecdotal. The mechanisms of leukemogenesis in DCL may be distinct from other types of leukemia. Possible causes of DCL include oncogenic alteration or premature aging of transplanted donor cells in an immunosuppressed person. Although many studies have recently better characterized leukemic stem cells, it is important to also consider that both intrinsic cell factors and external signals from the hematopoietic microenvironment govern the developmental fate of hematopoietic stem cells (HSCs). Therefore, in cases of DCL, alteration of the microenvironment after HCT may increase the likelihood that some progeny of normal HSCs become leukemic. This complex intercommunication between cells, growth factors, and cytokines in the hematopoietic microenvironment are critical to balance HSC self-renewal, proliferation, and differentiation. However, this homeostasis is likely perturbed in the development of DCL, allowing unique insight into the stimuli that regulate normal and potentially abnormal hematopoietic development. In this article, we discuss the possible pathogenesis of DCL, its association with stem cells, and its likely dependence on a less-supportive stem cell niche.
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Feng, Qin, Ping Yi, Jiemin Wong, and Bert W. O'Malley. "Signaling within a Coactivator Complex: Methylation of SRC-3/AIB1 Is a MolecularSwitch for Complex Disassembly." Molecular and Cellular Biology 26, no. 21 (November 1, 2006): 7846–57. http://dx.doi.org/10.1128/mcb.00568-06.
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ABSTRACT Recent studies indicate that steroid receptor-mediated transcriptional initiation is a cyclical process involving multiple rounds of coactivator assembly and disassembly. Steroid receptor coactivator 3 (SRC-3) coactivator phosphorylation has been shown to regulate coactivator complex assembly, but the mechanisms by which coactivator disassembly is triggered are not well understood. In this study, we provide in vitro and in vivo evidence that members of the SRC coactivator family serve as substrates for the enzymatic coactivator coactivator-associated arginine methyltransferase 1 (CARM1). Methylation of SRC-3 was localized to an arginine in its CARM1 binding region and correlated with decreased estrogen receptor alpha-mediated transcription, as seen with both cell-based and in vitro transcription assays. Consistent with this finding, we demonstrated that methylation promotes dissociation of the SRC-3/CARM1 coactivator complex. Methylation of SRC-3 is regulated by estrogen signaling in MCF7 cells and serves as a molecular switch for disassembly of the SRC-3 transcriptional coactivator complex. We propose that CARM1 is a dual-function coactivator, as it not only activates transcription by modifying core histone tails but also terminates hormone signaling by disassembly of the coactivator complex.
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Kinzler, Eric R., and Teresa Compton. "Characterization of Human Cytomegalovirus Glycoprotein-Induced Cell-Cell Fusion." Journal of Virology 79, no. 12 (June 15, 2005): 7827–37. http://dx.doi.org/10.1128/jvi.79.12.7827-7837.2005.
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ABSTRACT Human cytomegalovirus (CMV) infection is dependent on the functions of structural glycoproteins at multiple stages of the viral life cycle. These proteins mediate the initial attachment and fusion events that occur between the viral envelope and a host cell membrane, as well as virion-independent cell-cell spread of the infection. Here we have utilized a cell-based fusion assay to identify the fusogenic glycoproteins of CMV. To deliver the glycoprotein genes to various cell lines, we constructed recombinant retroviruses encoding gB, gH, gL, and gO. Cells expressing individual CMV glycoproteins did not form multinucleated syncytia. Conversely, cells expressing gH/gL showed pronounced syncytium formation, although expression of gH or gL alone had no effect. Anti-gH neutralizing antibodies prevented syncytium formation. Coexpression of gB and/or gO with gH/gL did not yield detectably increased numbers of syncytia. For verification, these results were recapitulated in several cell lines. Additionally, we found that fusion was cell line dependent, as nonimmortalized fibroblast strains did not fuse under any conditions. Thus, the CMV gH/gL complex has inherent fusogenic activity that can be measured in certain cell lines; however, fusion in fibroblast strains may involve a more complex mechanism involving additional viral and/or cellular factors.
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Anderson, Amy L., Romeo Sporici, John Lambris, David LaRosa, and Arnold I. Levinson. "Pathogenesis of B-Cell Superantigen-Induced Immune Complex-Mediated Inflammation." Infection and Immunity 74, no. 2 (February 2006): 1196–203. http://dx.doi.org/10.1128/iai.74.2.1196-1203.2006.
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ABSTRACT Staphylococcal protein A (SpA) is representative of a new class of antigens, the B-cell superantigens (SAgs). These antigens bind to the Fab regions of immunoglobulin molecules outside their complementarity-determining regions. SpA, the best-studied B-cell SAg, reacts with the Fabs of most VH3+ immunoglobulins, which are expressed on 30 to 60% of human peripheral B cells. Therefore, B-cell SAgs like SpA have great potential to elicit inflammatory responses in vivo. We previously reported that the interaction of SpA with VH3+ immunoglobulin molecules leads to activation of the complement cascade and produces a histologic pattern of inflammation in the skin of a rabbit indicative of immune complex injury. To elucidate the cellular and molecular events contributing to this type of unconventional immune complex-mediated inflammation, we established a mouse peritoneal Arthus reaction model. Mice treated intravenously with human polyclonal immunoglobulin G (IgG), followed by intraperitoneal injection of SpA, showed neutrophil influx into the peritoneal cavity with peak numbers appearing at 8 h. This inflammatory reaction was dependent on the interaction of SpA with VH3+ IgG. Mast cells, FcγRIII, complement components, and tumor necrosis factor alpha play obligatory roles, and the reaction is associated with the local release of the CXC chemokines macrophage inflammatory protein 2 and KC. The data provide further compelling evidence for the induction of immune complex-mediated injury by a B-cell SAg and highlight important factors contributing to the pathogenesis of this novel type of inflammatory reaction.
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Reeves, Wendy M., and Steven Hahn. "Activator-Independent Functions of the Yeast Mediator Sin4 Complex in Preinitiation Complex Formation and Transcription Reinitiation." Molecular and Cellular Biology 23, no. 1 (January 1, 2003): 349–58. http://dx.doi.org/10.1128/mcb.23.1.349-358.2003.
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ABSTRACT RNA polymerase II (Pol II) Mediator plays an essential role in both basal and activated transcription. Previously, subunits of the Sin4 Mediator complex (Sin4, Pgd1, Gal11, and Med2) have been implicated in both positive and negative transcriptional regulation. Furthermore, it was proposed that this subcomplex constitutes an activator-binding domain. A yeast nuclear-extract system was used to investigate the biochemical role of the Sin4 complex. In contrast to previous findings, we found at least two general activator-independent roles for the Sin4 complex. First, mutations in sin4 and pgd1 destabilized the Pol II-Med complex, leading to a reduced rate and extent of preinitiation complex (PIC) formation both in the presence and absence of activators. Although reduced in amount compared with the wild type, PICs that are formed lacking the Sin4 complex are stable and can initiate transcription normally. Second, mutation of pgd1 causes partial disruption of the Sin4 complex and leads to a defect in transcription reinitiation. This defect is caused by dissociation of mutant Mediator from promoters after initiation, leading to nonfunctional Scaffold complexes. These results show that function of the Sin4 complex is not essential for transcription activation in a crude in vitro system but that it plays key roles in the general transcription mechanism.
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Spitzer, H., and S. Hochstein. "Simple- and complex-cell response dependences on stimulation parameters." Journal of Neurophysiology 53, no. 5 (May 1, 1985): 1244–65. http://dx.doi.org/10.1152/jn.1985.53.5.1244.
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We studied the response time course and amplitude dependence on stimulation parameters in cat cortical visual neurons to determine their receptive-field spatial-summation characteristics. Response poststimulus time (PST) histograms of cortical simple cells to contrast-reversal grating stimulation generally have a single peak for each stimulus temporal cycle, though the responses appear rectified. In response to contrast-reversal grating stimulation the general PST histogram time course for complex cells is two peaks, though often these peaks are of different amplitudes. The time course of complex-cell responses, and the ratio of these two response peaks often varies with stimulation parameters. The appearance of a single response peak in simple cells is reflected in the dominance of the odd harmonic Fourier portion, whereas the half-wave rectification leads to a considerable even harmonic portion. Still, this even portion is never significantly greater than the odd portion. When complex cell PST histograms have two nearly equal peaks, Fourier transformation reveals almost only even harmonic components. When the histogram contains two peaks of unequal amplitude Fourier analysis reveals large odd and even components. An even:odd Fourier harmonic portion ratio larger than 1 may be seen as a defining characteristic of complex cells, differentiating them from simple cells. Histograms with two unequal peaks appear "mixed," containing something of the "pure" single-peaked response and something of the pure double-peaked response. The degree to which the response is mixed may be measured by the ratio of the even:odd portion amplitudes. There is a great degree of variability with stimulation parameters (both spatial phase and spatial frequency) of the time course of mixed responses as opposed to the case of responses that have two equal peaks independent of stimulation grating phase and frequency. In both simple and complex cells there is a close coincidence of the spatial frequency ranges over which the even and odd portions are substantial, though many complex cells show a periodic variation of the even:odd portions ratio. This spatial-frequency dependence differs from that of LGN Y-cells where the odd portion dominates at low spatial frequencies and the even portion at high spatial frequencies. The ratio of even-to-odd portion cut-off is close to 3:1 in all Y-cells, a characteristic we did not find in cortical simple or complex cells. We suggest, therefore, that the nonlinearity of these complex cells does not derive from that of Y-cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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Unsoeld, Heike, and Hanspeter Pircher. "Complex Memory T-Cell Phenotypes Revealed by Coexpression of CD62L and CCR7." Journal of Virology 79, no. 7 (April 1, 2005): 4510–13. http://dx.doi.org/10.1128/jvi.79.7.4510-4513.2005.
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ABSTRACT Antigen-experienced T cells have been divided into CD62L+ CCR7+ central memory (TCM) and CD62L− CCR7− effector memory (TEM) cells. Here, we examined coexpression of CD62L and CCR7 in lymphocytic choriomeningitis virus-specific memory CD8 T cells from both lymphoid and nonlymphoid tissues. Three main points emerged: firstly, memory cells frequently expressed a mixed CD62L− CCR7+ phenotype that differed from the phenotypes of classical TEM and TCM cells; secondly, TCM cells were not restricted to lymphoid organs but were also present in significant numbers in nonlymphoid tissues; and thirdly, a major shift from a TCM to TEM phenotype was found in memory cells that had been stimulated repetitively with antigen.
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Shin, Jinwook, Hongjie Pan, and Xiao-Ping Zhong. "Regulation of mast cell survival and function by tuberous sclerosis complex 1." Blood 119, no. 14 (April 5, 2012): 3306–14. http://dx.doi.org/10.1182/blood-2011-05-353342.
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Abstract Mast cells play critical roles in allergic disorders and asthma. The importance of tuberous sclerosis complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) signaling in mast cells is unknown. Here, we report that TSC1 is a critical regulator for mTOR signaling in mast cells downstream of FcεRI and c-Kit, and differentially controls mast cell degranulation and cytokine production. TSC1-deficiency results in impaired mast cell degranulation, but enhanced cytokine production in vitro and in vivo after FcεRI engagement. Furthermore, TSC1 is critical for mast cell survival through multiple pathways of apoptosis including the down-regulation of p53, miR-34a, reactive oxygen species, and the up-regulation of Bcl-2. Together, these findings reveal that TSC1 is a critical regulator of mast cell activation and survival, suggesting the manipulation of the TSC1/2-mTOR pathway as a therapeutic strategy for mast cell-mediated diseases.
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Brown, Nat F., Justin A. Boddey, Cameron P. Flegg, and Ifor R. Beacham. "Adherence of Burkholderia pseudomallei Cells to Cultured Human Epithelial Cell Lines Is Regulated by Growth Temperature." Infection and Immunity 70, no. 2 (February 2002): 974–80. http://dx.doi.org/10.1128/iai.70.2.974-980.2002.
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ABSTRACT We have investigated the adherence of Burkholderia pseudomallei, cultured under a number of different conditions, to six human epithelial cell lines. While several complex medium compositions had relatively little effect on adherence, growth at 30°C was found to significantly increase adherence to all cell lines relative to that of cultures grown at 37°C (P < 0.001).
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Rezaie, Alireza R. "Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex." Blood 97, no. 8 (April 15, 2001): 2308–13. http://dx.doi.org/10.1182/blood.v97.8.2308.
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Abstract Heparin is a commonly used anticoagulant drug. It functions primarily by accelerating the antithrombin inhibition of coagulation proteinases, among which factor Xa and thrombin are believed to be the most important targets. There are conflicting results as to whether anticoagulant heparins can catalyze the antithrombin inhibition of factor Xa in the prothrombinase complex (factor Va, negatively charged membrane surfaces, and calcium ion), which is the physiologically relevant form of the proteinase responsible for the activation of prothrombin to thrombin during the blood coagulation process. In this study, a novel assay system was developed to compare the catalytic effect of different molecular-weight heparins in the antithrombin inhibition of factor Xa, either in free form or assembled into the prothrombinase complex during the process of prothrombin activation. This assay takes advantage of the unique property of a recombinant mutant antithrombin, which, similar to the wild-type antithrombin, rapidly inhibits factor Xa, but not thrombin, in the presence of heparin. A direct prothrombinase inhibition assay, monitoring thrombin generation under near physiological concentrations of prothrombin and antithrombin in the presence of therapeutic doses of low- and high-molecular-weight heparins, indicates that factor Xa in the prothrombinase complex is protected from inhibition by antithrombin more than 1000 times, independent of the molecular size of heparin.
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Ryu, Jae Ryun, Asier Echarri, Ran Li, and Ann Marie Pendergast. "Regulation of Cell-Cell Adhesion by Abi/Diaphanous Complexes." Molecular and Cellular Biology 29, no. 7 (January 21, 2009): 1735–48. http://dx.doi.org/10.1128/mcb.01483-08.
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ABSTRACT Actin polymerization provides the driving force for the formation of cell-cell junctions and is mediated by two types of actin nucleators, Arp2/3 and formins. Proteins required for coordinately linking cadherin-mediated adhesion to Arp2/3-dependent versus formin-dependent nucleation have yet to be defined. Here we show a role for Abi, the Abi-binding partner Nap1, and the Nap1-binding protein Sra1 in the regulation of cadherin-dependent adhesion. We found that Abi, which is known to interact with Wave, leading to activation of the Arp2/3 complex, is also capable of interacting with the Diaphanous (Dia)-related formins in the absence of Wave. Knockdown of Abi, Nap1, Sra1, or Dia markedly inhibited cell-cell junctions, whereas knockdown of Wave or Arp2/3 produced mild and transient phenotypes. Dia and Abi colocalized with β-catenin at cell-cell junctions. Further, Dia and Wave bound to overlapping sites on Abi1, and Wave competed with Dia for Abi1 binding. Notably, an active Dia1 C-terminal fragment that localizes to cell-cell junctions rescued the abnormal junctions induced by depletion of Abi or Nap1 in epithelial cells. These findings uncover a novel link between cadherin-mediated adhesion and the regulation of actin dynamics through the requirement for an Abi/Dia complex for the formation and stability of cell-cell junctions.
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Gaudenzio, Nicolas, Nicolas Espagnolle, Lennart T. Mars, Roland Liblau, Salvatore Valitutti, and Eric Espinosa. "Cell-cell cooperation at the T helper cell/mast cell immunological synapse." Blood 114, no. 24 (December 3, 2009): 4979–88. http://dx.doi.org/10.1182/blood-2009-02-202648.
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Abstract It has been suggested that mast cells might serve, under certain circumstances, as antigen-presenting cells (APCs) for T cells. However, whether cognate interactions between mast cells and class II–restricted CD4+ T cells actually occur is still an open question. We addressed this question by using peritoneal cell–derived mast cells (PCMCs) and freshly isolated peritoneal mast cells as APC models. Our results show that in vitro treatment of PCMCs with interferon-γ and interleukin-4 induced surface expression of mature major histocompatibility complex class II molecules and CD86. When interferon-γ/interleukin-4–primed PCMCs were used as APCs for CD4+ T cells, they induced activation of effector T cells but not of their naive counterparts as evidenced by CD69 up-regulation, proliferation, and cytokine production. Confocal laser scanning microscopy showed that CD4+ T cells formed immunological synapses and polarized their secretory machinery toward both antigen-loaded PCMCs and freshly isolated peritoneal mast cells. Finally, on cognate interaction with CD4+ T cells, mast cells lowered their threshold of activation via FcϵRI. Our results show that mast cells can establish cognate interactions with class II–restricted helper T cells, implying that they can actually serve as resident APCs in inflamed tissues.
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Chapuy, Bjoern, Stefano Monti, Kunihiko Takeyama, Scott J. Rodig, Yansheng Hao, Kelly T. Yeda, Haig Inguilizian, et al. "A Structural Basis for p53-Deficiency, Deregulated Cell Cycle and Unfavorable Outcome in Diffuse Large B-Cell Lymphoma." Blood 120, no. 21 (November 16, 2012): 1534. http://dx.doi.org/10.1182/blood.v120.21.1534.1534.
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Abstract Abstract 1534 + equal contributions Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease with a high proliferation rate and infrequent somatic mutations of TP53 and genes encoding cell cycle pathway components. Despite recent advances in the molecular understanding of DLBCL pathogenesis, clinical models such as the International Prognostic Index (IPI) are still used to identify high-risk patients. By integrating high-resolution high-density SNP array data with transcriptional profiles and performing pathway analysis in 180 primary DLBCLs, we identified a comprehensive set of copy number alterations (CNAs) that decreased p53 activity and perturbed cell cycle regulation. Primary DLBCLs with single copy loss of 17p13.1 (TP53/RPL26/KDM6B) often had CNAs of an additional p53 modifier – 9p21.3 (CDKN2A/ARF), 19q13.42 (BCL2L12), 12q15 (MDM2) or 1q23.3 (MDM4/RFWD2). CNAs of the respective p53 modifiers, CDKN2A (ARF, 9p21.3), MDM2 (12q15) and MDM4/RFWD2 (1q23.3), occurred in largely separate groups of tumors. DLBCLs with CNAs of p53 pathway members frequently exhibited concurrent alterations of additional cell cycle components such as CCND3 (6p21.32), CDK6 (7q22.1), CDK2/CDK4 (12q15) and/or RB1 (13q14.2) or RBL2 (16q12.2). When the primary DLBCLs were clustered in the space of CNAs that perturb p53 pathway and cell cycle components, 66% of tumors had multiple alterations (“complex” pattern) whereas the remaining 34% of tumors lacked these lesions (“clean” signature). Tumors with “complex” alterations of p53 pathway and cell cycle components also had more total CNAs and more frequent TP53 mutations, highlighting the association between p53 deficiency, cell cycle deregulation and increased genomic instability in DLBCL. The patterns of “complex” vs. “clean” CNAs of p53 pathway and cell cycle components and the association between the “complex” signature and total CNAs were confirmed in an independent series of primary DLBCLs. To further characterize DLBCLs with “complex” vs. “clean” CNA patterns, we performed gene set enrichment analyses with publicly available series of p53 target genes and a RB-deficiency gene set which included multiple E2F targets. The p53 target transcripts were significantly less abundant in “complex” DLBCLs, directly linking their genetic signature of p53 deficiency with decreased p53 activity. Furthermore, the RB-deficiency gene set was significantly enriched in “complex” DLBCLs suggesting that these tumors had increased E2F-mediated cell cycle progression. Consistent with these observations, DLBCLs with “complex” CNA patterns also had significantly higher proliferation indices as determined by Ki67 immunostaining. We next assessed the prognostic significance of the “complex” CNA pattern in the subset of patients who were treated with R-CHOP (rituxan, cyclophosphamide, adriamycin, oncovin, prednisone) and had long-term follow-up. R-CHOP treated patients with “complex” CNA patterns had a 5-year overall survival of only 62%; in contrast, those with “clean” CNA signatures had an 100% overall survival (p =.001). The association between CN complexity and outcome was independent of transcriptionally defined categories and additive to the clinical IPI risk model. Taken together, these data provide a structural basis for deregulated cell cycle, increased cellular proliferation and unfavorable outcome in DLBCL and suggest targeted treatment strategies. Disclosures: No relevant conflicts of interest to declare.
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Mundy, Cynthia L., Nadja Patenge, Adam G. W. Matthews, and Marjorie A. Oettinger. "Assembly of the RAG1/RAG2 Synaptic Complex." Molecular and Cellular Biology 22, no. 1 (January 1, 2002): 69–77. http://dx.doi.org/10.1128/mcb.22.1.69-77.2002.
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ABSTRACT Assembly of antigen receptor genes by V(D)J recombination requires the site-specific recognition of two distinct DNA elements differing in the length of the spacer DNA that separates two conserved recognition motifs. Under appropriate conditions, V(D)J cleavage by the purified RAG1/RAG2 recombinase is similarly restricted. Double-strand breakage occurs only when these proteins are bound to a pair of complementary signals in a synaptic complex. We examine here the binding of the RAG proteins to signal sequences and find that the full complement of proteins required for synapsis of two signals and coupled cleavage can assemble on a single signal. This complex, composed of a dimer of RAG2 and at least a trimer of RAG1, remains inactive for double-strand break formation until a second complementary signal is provided. Thus, binding of the second signal activates the complex, possibly by inducing a conformational change. If synaptic complexes are formed similarly in vivo, one signal of a recombining pair may be the preferred site for RAG1/RAG2 assembly.
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Dechassa, Mekonnen Lemma, Bei Zhang, Rachel Horowitz-Scherer, Jim Persinger, Christopher L. Woodcock, Craig L. Peterson, and Blaine Bartholomew. "Architecture of the SWI/SNF-Nucleosome Complex." Molecular and Cellular Biology 28, no. 19 (July 21, 2008): 6010–21. http://dx.doi.org/10.1128/mcb.00693-08.
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ABSTRACT The SWI/SNF complex disrupts and mobilizes chromatin in an ATP-dependent manner. SWI/SNF interactions with nucleosomes were mapped by DNA footprinting and site-directed DNA and protein cross-linking when SWI/SNF was recruited by a transcription activator. SWI/SNF was found by DNA footprinting to contact tightly around one gyre of DNA spanning ∼50 bp from the nucleosomal entry site to near the dyad axis. The DNA footprint is consistent with nucleosomes binding to an asymmetric trough of SWI/SNF that was revealed by the improved imaging of free SWI/SNF. The DNA site-directed cross-linking revealed that the catalytic subunit Swi2/Snf2 is associated with nucleosomes two helical turns from the dyad axis and that the Snf6 subunit is proximal to the transcription factor recruiting SWI/SNF. The highly conserved Snf5 subunit associates with the histone octamer and not with nucleosomal DNA. The model of the binding trough of SWI/SNF illustrates how nucleosomal DNA can be mobilized while SWI/SNF remains bound.
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Xing, Jun, Hilary M. Sheppard, Siska I. Corneillie, and Xuan Liu. "p53 Stimulates TFIID-TFIIA-Promoter Complex Assembly, and p53-T Antigen Complex Inhibits TATA Binding Protein-TATA Interaction." Molecular and Cellular Biology 21, no. 11 (June 1, 2001): 3652–61. http://dx.doi.org/10.1128/mcb.21.11.3652-3661.2001.
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ABSTRACT Simian virus 40 large T antigen has been shown to inhibit p53-mediated transcription once tethered to p53-responsive promoters through interaction with p53. In this study we report that p53 stimulates transcription by enhancing the recruitment of the basal transcription factors, TFIIA and TFIID, on the promoter (the DA complex) and by inducing a conformational change in the DA complex. Significantly, we have demonstrated that T antigen inhibits p53-mediated transcription by blocking this ability of p53. We investigated the mechanism for this inhibition and found that DA complex formation was resistant to T-antigen repression when the TFIID-DNA complex was formed prior to addition of p53-T antigen complex, indicating that the T antigen, once tethered to the promoter by p53, targets TFIID. Further, we have shown that the p53-T antigen complex prevents the TATA binding protein from binding to the TATA box. Thus, these data suggest a detailed mechanism by which p53 activates transcription and by which T antigen inhibits p53-mediated transcription.
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Smith, Edwin R., Christelle Cayrou, Rong Huang, William S. Lane, Jacques Côté, and John C. Lucchesi. "A Human Protein Complex Homologous to the Drosophila MSL Complex Is Responsible for the Majority of Histone H4 Acetylation at Lysine 16." Molecular and Cellular Biology 25, no. 21 (November 1, 2005): 9175–88. http://dx.doi.org/10.1128/mcb.25.21.9175-9188.2005.
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ABSTRACT We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. We also find that hMOF is a component of additional complexes, forming associations with host cell factor 1 and a protein distantly related to MSL1 (hMSL1v1). We find two versions of hMSL3 in the hMSL complex that differ by the presence of the chromodomain. Lastly, we find that reduction in the levels of hMSLs and acetylation of H4 at lysine 16 are correlated with reduced transcription of some genes and with a G2/M cell cycle arrest. This is of particular interest given the recent correlation of global loss of acetylation of lysine 16 in histone H4 with tumorigenesis.
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Dingwell, Kevin S., and David C. Johnson. "The Herpes Simplex Virus gE-gI Complex Facilitates Cell-to-Cell Spread and Binds to Components of Cell Junctions." Journal of Virology 72, no. 11 (November 1, 1998): 8933–42. http://dx.doi.org/10.1128/jvi.72.11.8933-8942.1998.
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ABSTRACT The herpes simplex virus (HSV) glycoprotein complex gE-gI mediates the spread of viruses between adjacent cells, and this property is especially evident for cells that form extensive cell junctions, e.g., epithelial cells, fibroblasts, and neurons. Mutants lacking gE or gI are not compromised in their ability to enter cells as extracellular viruses. Therefore, gE-gI functions specifically in the movement of virus across cell-cell contacts and, as such, provides a molecular handle on this poorly understood process. We expressed gE-gI in human epithelial cells by using replication-defective adenovirus (Ad) vectors. gE-gI accumulated at lateral surfaces of the epithelial cells, colocalizing with the adherens junction protein β-catenin but was not found on either the apical or basal plasma membranes and did not colocalize with ZO-1, a component of tight junctions. In subconfluent monolayers, gE-gI was found at cell junctions but was absent from those lateral surfaces not in contact with another cell, as was the case for β-catenin. Similar localization of gE-gI to cell junctions was observed in HSV-infected epithelial cells. By contrast, HSV glycoprotein gD, expressed using a recombinant Ad vectors, was found primarily along the apical surfaces of cells, with little or no protein found on the basal or lateral surfaces. Expression of gE-gI without other HSV polypeptides did not cause redistribution of either ZO-1 or β-catenin or alter tight-junction functions. Together these results support a model in which gE-gI accumulates at sites of cell-cell contact by interacting with junctional components. We hypothesize that gE-gI mediates transfer of HSV across cell junctions by virtue of these interactions with cell junction components.
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Ekkens, Melinda J., Devon J. Shedlock, EuiHye Jung, Amy Troy, Erika L. Pearce, Hao Shen, and Edward J. Pearce. "Th1 and Th2 Cells Help CD8 T-Cell Responses." Infection and Immunity 75, no. 5 (February 26, 2007): 2291–96. http://dx.doi.org/10.1128/iai.01328-06.
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ABSTRACT Help from CD4 T cells is often important for the establishment of primary and memory CD8 T-cell responses. However, it has yet to be determined whether T helper polarization affects the delivery of help and/or whether responding CD8 T cells helped by Th1 or Th2 cells express distinct effector properties. To address these issues, we compared CD8 T-cell responses in the context of Th1 or Th2 help by injecting dendritic cells copulsed with the major histocompatibility complex class I-restricted OVA peptide plus, respectively, bacterial or helminth antigens. We found that Th2 cells, like Th1 cells, can help primary and long-lived memory CD8 T-cell responses. Experiments in interleukin-12 (IL-12)−/− and IL-4−/− mice, in which polarized Th1 or Th2 responses, respectively, fail to develop, indicate that the underlying basis of CD4 help is independent of attributes acquired as a response to polarization.
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Dai, Yulin, Ruifeng Hu, Astrid Marilyn Manuel, Andi Liu, Peilin Jia, and Zhongming Zhao. "CSEA-DB: an omnibus for human complex trait and cell type associations." Nucleic Acids Research 49, no. D1 (November 19, 2020): D862—D870. http://dx.doi.org/10.1093/nar/gkaa1064.
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Abstract During the past decade, genome-wide association studies (GWAS) have identified many genetic variants with susceptibility to several thousands of complex diseases or traits. The genetic regulation of gene expression is highly tissue-specific and cell type-specific. Recently, single-cell technology has paved the way to dissect cellular heterogeneity in human tissues. Here, we present a reference database for GWAS trait-associated cell type-specificity, named Cell type-Specific Enrichment Analysis DataBase (CSEA-DB, available at https://bioinfo.uth.edu/CSEADB/). Specifically, we curated total of 5120 GWAS summary statistics data for a wide range of human traits and diseases followed by rigorous quality control. We further collected >900 000 cells from the leading consortia such as Human Cell Landscape, Human Cell Atlas, and extensive literature mining, including 752 tissue cell types from 71 adult and fetal tissues across 11 human organ systems. The tissues and cell types were annotated with Uberon and Cell Ontology. By applying our deTS algorithm, we conducted 10 250 480 times of trait-cell type associations, reporting a total of 598 (11.68%) GWAS traits with at least one significantly associated cell type. In summary, CSEA-DB could serve as a repository of association map for human complex traits and their underlying cell types, manually curated GWAS, and single-cell transcriptome resources.
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Knight, Jason S., Nikhil Sharma, and Erle S. Robertson. "SCFSkp2 Complex Targeted by Epstein-Barr Virus Essential Nuclear Antigen." Molecular and Cellular Biology 25, no. 5 (March 1, 2005): 1749–63. http://dx.doi.org/10.1128/mcb.25.5.1749-1763.2005.
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ABSTRACT The stability of cell cycle checkpoint and regulatory proteins is controlled by the ubiquitin-proteasome degradation machinery. A critical regulator of cell cycle molecules is the E3 ubiquitin ligase SCFSkp2, known to facilitate the polyubiquitination and degradation of p27, E2F, and c-myc. SCFSkp2 is frequently deregulated in human cancers. In this study, we have revealed a novel link between the essential Epstein-Barr virus (EBV) nuclear antigen EBNA3C and the SCFSkp2 complex, providing a mechanism for cell cycle regulation by EBV. EBNA3C associates with cyclin A/cdk2 complexes, disrupting the kinase inhibitor p27 and enhancing kinase activity. The recruitment of SCFSkp2 activity to cyclin A complexes by EBNA3C results in ubiquitination and SCFSkp2-dependent degradation of p27. This is the first report of a viral protein usurping the function of the SCFSkp2 cell cycle regulatory machinery to regulate p27 stability, establishing the foundation for a mechanism by which EBV regulates cyclin/cdk activity in human cancers.
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Raulet, David H. "Natural Killer Cells Adapt to Major Histocompatibility Complex: Implications for Hematopoietic Cell Transplantation." Blood 124, no. 21 (December 6, 2014): SCI—26—SCI—26. http://dx.doi.org/10.1182/blood.v124.21.sci-26.sci-26.
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Abstract Natural Killer (NK) cells play several important roles in hematopoietic cell transplantation. Host NK cells can reject allogeneic transplants that lack major histocompatibility complex (MHC) molecules of the host (so-called “missing self” reactivity), whereas donor NK cells in the marrow can promote engraftment, inhibit graft versus host disease, and mediate rejection of host leukemic cells (graft versus tumor (GVT) response). Like T cells, NK cells can distinguish allogeneic cells from self-cells, and “learn” self vs. non-self so as to establish self-tolerance. This presentation will summarize current understanding of some of these processes based primarily on studies in mice, and present new data that may be relevant for the success of human bone marrow transplantation. The self-tolerance of T cells and B cells is established in large part by developmental processes that either remove or suppress self-reactive clones as the cells differentiate from hematopoietic stem cells. Studies will be presented that show that NK cell self-tolerance is regulated quite differently, by an adaptation process that occurs quite rapidly and acts on mature NK cells. NK cell reactivity against susceptible untransformed cells (e.g., cells from animals lacking MHC of the NK cell donor) is rapidly lost after transfer of such NK cells to susceptible hosts, indicating that self-tolerance is an adaptation that occurs rapidly under non-inflammatory conditions. Irradiation chimeras were employed to identify the cell types that induce tolerance of NK cells to cells from MHC-deficient mice, as one model of missing self-recognition. Stable tolerance of wild type NK cells to MHC-deficient cells was established when NK cells were exposed in chimeras to either MHC-deficient hematopoietic cells or MHC-deficient non-hematopoietic cells. Interestingly, however, tolerance induced by exposure solely to MHC-deficient hematopoietic cells was unstable in the face of inflammatory conditions arising from infections or exposures to inflammatory cytokines in vivo. Specifically, mixed chimeras consisting of WT and MHC-deficient hematopoietic cells in WT hosts were stably chimeric until the mice were exposed to viral or bacterial infections, at which time the MHC-deficient cells were rapidly eliminated. In contrast, tolerance induced by non-hematopoietic cells was much more stable. Specifically, mixed chimeras consisting of WT and MHC-deficient hematopoietic cells in MHC-deficient hosts were stably chimeric whether or not they underwent infections. These findings suggest that tolerance may be imposed by multiple mechanisms depending on the cell types that induce tolerance, with distinct properties as a result. Most importantly from a clinical perspective, the results suggest that depending on the host/donor combination, intense infections may jeopardize the stability of bone marrow transplants. Previous studies have shown that tolerance of NK cells to MHC-deficient cells is accompanied by a state of hyporesponsiveness of the NK cells, characterized by low functional responses to stimulation via crosslinking of activating receptors ex vivo. Accordingly, it has been widely accepted that hyporesponsiveness to stimulation is the mechanism of NK cell self-tolerance when NK cells lack inhibitory receptors specific for host MHC molecules. However, our recent analysis of chimeric NK cells showed that this cannot be the sole explanation. When NK cells developed in MHC+ hosts in the presence of MHC-deficient hematopoietic cells, the cells became responsive to activating receptor stimulation despite being tolerant of MHC-deficient cells. Hence, tolerance can occur even when NK cells are responsive to stimulation. In contrast, when NK cells developed in MHC-deficient hosts, they became hyporesponsive. These data suggest that non-hematopoietic cells in the host impart hyporesponsiveness. Furthermore, exposure to MHC-deficient hematopoietic cells induces tolerance by a mechanism distinct from hyporesponsiveness. The latter mechanism is relatively unstable as it can be broken as a result of infections. Disclosures Raulet: Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy.
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Papadopoulos, Nikolaos, Parra R. Gonzalo, and Johannes Söding. "PROSSTT: probabilistic simulation of single-cell RNA-seq data for complex differentiation processes." Bioinformatics 35, no. 18 (February 1, 2019): 3517–19. http://dx.doi.org/10.1093/bioinformatics/btz078.
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Abstract Summary Cellular lineage trees can be derived from single-cell RNA sequencing snapshots of differentiating cells. Currently, only datasets with simple topologies are available. To test and further develop tools for lineage tree reconstruction, we need test datasets with known complex topologies. PROSSTT can simulate scRNA-seq datasets for differentiation processes with lineage trees of any desired complexity, noise level, noise model and size. PROSSTT also provides scripts to quantify the quality of predicted lineage trees. Availability and implementation https://github.com/soedinglab/prosstt. Supplementary information Supplementary data are available at Bioinformatics online.
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Jeffries, Shawn, David J. Robbins, and Anthony J. Capobianco. "Characterization of a High-Molecular-Weight Notch Complex in the Nucleus of Notchic-Transformed RKE Cells and in a Human T-Cell Leukemia Cell Line." Molecular and Cellular Biology 22, no. 11 (June 1, 2002): 3927–41. http://dx.doi.org/10.1128/mcb.22.11.3927-3941.2002.
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ABSTRACT Notch genes encode a family of transmembrane proteins that are involved in many cellular processes, such as differentiation, proliferation, and apoptosis. It is well established that all four Notch genes can act as oncogenes; however, the mechanism by which Notch proteins transform cells remains unknown. Previously, we reported that both nuclear localization and transcriptional activation are required for neoplastic transformation of RKE cells. Furthermore, we identified cyclin D1 as a direct transcriptional target of constitutively active Notch molecules. In an effort to understand the mechanism by which Notch functions in the nucleus, we sought to determine if Notch formed stable complexes using size exclusion chromatography. Herein, we report that the Notch intracellular domain (Nic) forms distinct high-molecular-weight complexes in the nuclei of transformed RKE cells. The largest complex is approximately 1.5 MDa and contains both endogenous CSL (for CBF1, Suppressor of Hairless, and Lag-1) and Mastermind-Like-1 (Maml). Nic molecules that do not have the high-affinity binding site for CSL (RAM) retain the ability to associate with CSL in a stable complex through interactions involving Maml. However, Maml does not directly bind to CSL. Furthermore, Maml can rescue ΔRAM transcriptional activity on a CSL-dependent promoter. These results indicate that deletion of the RAM domain does not equate to CSL-independent signaling. Moreover, in SUP-T1 cells, Nic exists exclusively in the largest Nic-containing complex. SUP-T1 cells are derived from a T-cell leukemia that harbors the t(7;9)(q34;q34.3) translocation and constitutively express Nic. Taken together, our data indicate that complex formation is likely required for neoplastic transformation by Notchic.