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Jesus Duque-Afonso, Chiou-Hong Lin, Kyuho Han, Michael C Wei, Jue Feng, Jason Kurzer, Corina Schneidawind, Stephen H K Wong, Michael C Bassik, Michael L Cleary
There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL which result in hyperactivation of the key oncogenic effector enzyme PLCγ2...
October 7, 2016: Cancer Research
Eun-Kyung Kwon, Chan-Ki Min, Yuri Kim, Jae-Won Lee, Abdimadiyeva Aigerim, Sebastian Schmidt, Hyun-Jun Nam, Seong Kyu Han, Kuglae Kim, Jeong Seok Cha, Hoyoung Kim, Sanguk Kim, Hyun-Soo Cho, Myung-Sik Choi, Nam-Hyuk Cho
Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown...
October 15, 2016: Biochimica et Biophysica Acta
Tiantian Luo, Jing Hu, Dan Xi, Haowei Xiong, Wenshuai He, Jichen Liu, Menghao Li, Hao Lu, Jinzhen Zhao, Wenyan Lai, Zhigang Guo
Previously, we reported that heat shock protein (HSP)65 impairs the effects of high-density lipoprotein on macrophages. We also showed that immune response activation adversely affects reverse cholesterol transport (RCT). In this study, we investigated the effects of the Src family kinase lymphocyte-specific protein tyrosine kinase (Lck) and elucidated the mechanism underlying HSP65-regulated cholesterol efflux in T cells. We evaluated cell proliferation, Lck expression, and inflammatory cytokine production in Jurkat cells and CD4(+) T cells...
October 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Neel H Shah, Qi Wang, Qingrong Yan, Deepti Karandur, Theresa A Kadlecek, Ian R Fallahee, William P Russ, Rama Ranganathan, Arthur Weiss, John Kuriyan
The sequence of events that initiates T cell signaling is dictated by the specificities and order of activation of the tyrosine kinases that signal downstream of the T cell receptor. Using a platform that combines exhaustive point-mutagenesis of peptide substrates, bacterial surface-display, cell sorting, and deep sequencing, we have defined the specificities of the first two kinases in this pathway, Lck and ZAP-70, for the T cell receptor ζ chain and the scaffold proteins LAT and SLP-76. We find that ZAP-70 selects its substrates by utilizing an electrostatic mechanism that excludes substrates with positively-charged residues and favors LAT and SLP-76 phosphosites that are surrounded by negatively-charged residues...
October 4, 2016: ELife
Birthe Trautz, Virginia Pierini, Rebecka Wombacher, Bettina Stolp, Amanda J Chase, Massimo Pizzato, Oliver T Fackler
: SERINC 3 and 5 are recently identified host cell inhibitors of HIV-1 particle infectivity that are counteracted by the viral pathogenesis factor Nef. Here we confirm that HIV-1 Nef, but not HIV-1 Vpu, antagonizes the particle infectivity restriction of SERINC5. SERINC5 antagonism occurred in parallel to other Nef activities including cell surface receptor downregulation, trans-Golgi-network targeting of Lck and inhibition of host cell actin dynamics. Interaction motifs with host cell endocytic machinery, Nef-associated kinase complex as well as CD4 cytoplasmic tail/HIV-1 protease were identified as essential Nef determinants for SERINC5 antagonism...
September 28, 2016: Journal of Virology
Jing Deng, Yu-Ya Mitsuki, Guomiao Shen, Jocelyn Ray, Claudia Cicala, James Arthos, Michael L Dustin, Catarina E Hioe
: HIV is transmitted most efficiently from cell to cell and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events...
September 14, 2016: Journal of Virology
Fumihiro Niwa, Shigeo Sakuragi, Ayana Kobayashi, Shin Takagi, Yoichi Oda, Hiroko Bannai, Katsuhiko Mikoshiba
Calcium (Ca(2+)) is a versatile intracellular second messenger that operates in various signaling pathways leading to multiple biological outputs. The diversity of spatiotemporal patterns of Ca(2+) signals, generated by the coordination of Ca(2+) influx from the extracellular space and Ca(2+) release from the intracellular Ca(2+) store the endoplasmic reticulum (ER), is considered to underlie the diversity of biological outputs caused by a single signaling molecule. However, such Ca(2+) signaling diversity has not been well described because of technical limitations...
October 7, 2016: Biochemical and Biophysical Research Communications
John C Moore, Timothy S Mulligan, Nora Torres Yordán, Daniel Castranova, Van N Pham, Qin Tang, Riadh Lobbardi, Anthony Anselmo, Robert S Liwski, Jason N Berman, Ruslan I Sadreyev, Brant M Weinstein, David M Langenau
The zeta-chain (TCR) associated protein kinase 70kDa (ZAP70) is required for T-cell activation. ZAP70 deficiencies in humans and null mutations in mice lead to severe combined immunodeficiency. Here, we describe a zap70 loss-of-function mutation in zebrafish (zap70(y442)) that was created using TALENs. In contrast to what has been reported in morphant zebrafish, zap70(y442) homozygous mutant zebrafish displayed normal development of blood and lymphatic vasculature. Hematopoietic cell development was also largely unaffected in mutant larvae...
September 6, 2016: Molecular and Cellular Biology
Ruizhen Li, Julie Leblanc, Kevin He, X Johné Liu
Intracellular calcium transients are a universal phenomenon at fertilization and are required for egg activation, but the exact role of Ca(2+) in second polar body emission remains unknown. On the other hand, similar calcium transients have not been demonstrated during oocyte maturation and, yet, manipulating intracellular calcium levels interferes with first polar body emission, in mice and frogs. To determine the precise role of calcium signaling in polar body formation, we used live cell imaging coupled with temporally precise intracellular calcium buffering...
August 31, 2016: Molecular Biology of the Cell
Jessica T Leonard, Joelle S J Rowley, Christopher A Eide, Elie Traer, Brandon Hayes-Lattin, Marc Loriaux, Stephen E Spurgeon, Brian J Druker, Jeffrey W Tyner, Bill H Chang
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies...
August 31, 2016: Science Translational Medicine
Jin Tao, Yan Nie, Yuanyuan Hou, Xiaoyao Ma, Guoyu Ding, Jie Gao, Min Jiang, Gang Bai
Jie-Geng-Tang (JGT), a classic and famous traditional Chinese medicine (TCM) prescription composed of Platycodon grandiflorum (Jacq.) A. DC. (PG) and Glycyrrhiza uralensis Fisch. (GU), is well known for "clearing heat and relieving toxicity" and its ability to "diffuse the lung and relieve sore throat." However, the mechanism underlying its action remains unclear. In this study, potential anti-inflammatory ingredients were screened and submitted to PharmMapper and the KEGG bioinformatics website to predict the target proteins and related pathways, respectively...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
Hyoung-Min Han, Seung-Ju Kim, Jong-Sik Kim, Bum Hoi Kim, Hai Woong Lee, Yong Tae Lee, Kyung-Hwa Kang
Artemisia argyi Folium has been used to treat skin diseases, including eczema and dermatitis, in South Korean medicine. The present study investigated the curative effects of Artemisia argyi Folium extract (AAFE) on 2,4‑dinitrochlorobenzene (DNCB)‑induced atopic dermatitis (AD)‑like skin lesions in a BALB/c mouse model. Briefly, the dorsal skin of the BALB/c mice was sensitized three times with DNCB, whereas the ears were challenged twice. Repeated treatment with DNCB induced AD‑like lesions. The effects of AAFE on AD‑like lesions were evaluated by clinical observation, histopathological analysis, immunohistochemistry and enzyme‑linked immunosorbent assay...
October 2016: Molecular Medicine Reports
Na-Ra Han, Phil-Dong Moon, Sun-Young Nam, Ka-Jung Ryu, Myoung-Schook Yoou, Jung-Hye Choi, Sung-Yeoun Hwang, Hyung-Min Kim, Hyun-Ja Jeong
This study investigated a salutary effect of atractylone (Atr) which is an active constituent of Pyeongwee-San (KMP6) on mast cell-mediated allergic reactions. Our previous report indicated that KMP6 regulated allergic reactions. Thus, this study sought to determine the potential of Atr in vitro models, compound 48/80-stimulated rat peritoneal mast cells (RPMCs), phorbol 12-myristate 13-acetate (PMA) plus A23187-stimulated human mast cell line (HMC-1) cells, and stem cell factor (SCF)-stimulated RPMCs as well as in vivo models, IgE-mediated passive cutaneous anaphylaxis (PCA), compound 48/80-induced systemic anaphylaxis, and compound 48/80-induced ear swelling...
October 25, 2016: Chemico-biological Interactions
Shinjiro Sakamoto, Shigeru Yutani, Shigeki Shichijo, Michi Morita, Akira Yamada, Kyogo Itoh, Masanori Noguchi
The immunological characteristics of carcinoma of unknown primary site (CUP) are not well established due to inclusion of heterogeneous types of metastatic tumors with the absence of any detectable primary site. We evaluated the immune responses in patients with histologically unfavorable CUP during personalized peptide vaccination (PPV). Ten patients with histologically unfavorable CUP who had been treated by PPV after chemotherapy failure were analyzed. In PPV treatment, up to four human leukocyte antigen-matched peptides of a total 31 peptides were selected according to preexisting host immunity before vaccination and administered subcutaneously...
October 2016: Cancer Immunology, Immunotherapy: CII
Jennifer A Rohrs, Pin Wang, Stacey D Finley
Lymphocyte-specific protein tyrosine kinase (LCK) is a key activator of T cells; however, little is known about the specific autoregulatory mechanisms that control its activity. We have constructed a model of LCK autophosphorylation and phosphorylation by the regulating kinase CSK. The model was fit to existing experimental data in the literature that presents an in vitro reconstituted membrane system, which provides more physiologically relevant kinetic measurements than traditional solution-based systems...
2016: Cellular and Molecular Bioengineering
Yifeng Sun, Likun Hou, Yu Yang, Huikang Xie, Yang Yang, Zhigang Li, Heng Zhao, Wen Gao, Bo Su
BACKGROUND: In this study, we investigated the contribution of a gene expression-based signature (composed of BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR) to survival prediction for early-stage lung adenocarcinoma categorized by the new International Association for the Study of Lung Cancer (IASLC)/the American Thoracic Society (ATS)/the European Respiratory Society (ERS) classification. We also aimed to verify whether gene signature improves the risk discrimination of IASLC/ATS/ERS classification in early-stage lung adenocarcinoma...
2016: OncoTargets and Therapy
Francisco Llavero, Alain Artaso, Hadriano M Lacerda, Luis A Parada, José L Zugaza
Recently, we have reported that the IL-2-stimulated T cells activate PKCθ in order to phosphorylate the serine residues of αPIX-RhoGEF, and to switch on the Rac1/PYGM pathway resulting in T cell migration and proliferation. However, the molecular mechanism connecting the activated IL-2-R with the PKCθ/αPIX/Rac1/PYGM pathway is still unknown. In this study, the use of a combined pharmacological and genetic approach identified Lck, a Src family member, as the tyrosine kinase phosphorylating PLCγ leading to Rac1 and PYGM activation in the IL-2-stimulated Kit 225 T cells via the PKCθ/αPIX pathway...
November 2016: Cellular Signalling
Berit Carow, Yu Gao, Jonathan Coquet, Marie Reilly, Martin E Rottenberg
Conditional gene targeting using the bacteriophage-derived Cre recombinase is widely applied for functional gene studies in mice. Mice transgenic for Cre under the control of the lck gene promoter are used to study the role of loxP-targeted genes in T cell development and function. In this article, we show a striking 65% reduction in cellularity, preferential development of γδ versus αβ T cells, and increased expression of IL-7R in the thymus of mice expressing Cre under the proximal lck promoter (lck-cre(+) mice)...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Y Jeffrey Chiang, Richard J Hodes
Expression of Lck, a T-cell lineage-specific tyrosine kinase critical for T-cell development and activation, can be mediated by either proximal or distal lck promoter. We generated BAC transgenic mice in which BAC lck promoter was deleted and bred these transgenes to an Lck knockout background. Lck-PROX mice, in which only the proximal promoter is functional, have maximal Lck protein and normal thymic development through CD4(-) CD8(-) double negative (DN) and CD4(+) CD8(+) double positive (DP) stages, but undetectable Lck later in development and reduced mature single positive thymocytes...
October 2016: European Journal of Immunology
Yan Qin, Deanne W Sammond, Esther Braselmann, Margaret C Carpenter, Amy E Palmer
Various fluorescent probes have been developed to reveal the biological functions of intracellular labile Zn(2+). Here, we present Green Zinc Probe (GZnP), a novel genetically encoded Zn(2+) sensor design based on a single fluorescent protein (single-FP). The GZnP sensor is generated by attaching two zinc fingers (ZF) of the transcription factor Zap1 (ZF1 and ZF2) to the two ends of a circularly permuted green fluorescent protein (cpGFP). Formation of ZF folds induces interaction between the two ZFs, which induces a change in the cpGFP conformation, leading to an increase in fluorescence...
October 21, 2016: ACS Chemical Biology
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