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Swaathi Jayaraman, Michele Doucet, Wen Min Lau, Scott L Kominsky
UNLABELLED: Previously, we identified the transcriptional coactivator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, CITED2 expression was stably reduced in the human breast cancer cell lines MDA-MB-231 and MDA-MB-468, which are metastatic in animal models...
August 2016: Molecular Cancer Research: MCR
Han C Dan, Aaron Ebbs, Manolis Pasparakis, Terry Van Dyke, Daniela S Basseres, Albert S Baldwin
The serine/threonine protein kinase Akt promotes cell survival, growth, and proliferation through phosphorylation of different downstream substrates. A key effector of Akt is the mammalian target of rapamycin (mTOR). Akt is known to stimulate mTORC1 activity through phosphorylation of tuberous sclerosis complex 2 (TSC2) and PRAS40, both negative regulators of mTOR activity. We previously reported that IκB kinase α (IKKα), a component of the kinase complex that leads to NF-κB activation, plays an important role in promoting mTORC1 activity downstream of activated Akt...
September 5, 2014: Journal of Biological Chemistry
Ling-Jun Ho, Wen-Liang Chang, Ann Chen, Ping Chao, Jenn-Haung Lai
BACKGROUND: For thousands of years, it remains unclear why Chinese prefer complex herbal remedy and seldom try to purify it. One of the reasons is that they believe Chinese herbs compared to Western drugs are relatively less toxic and better tolerated. The so called "Junn-Chenn-Zuou-SS" theory illustrates a concept of coordinated effects from a combination of different Chinese herbs. PG27, a refined extract from a well-known Chinese antirheumatic herb Tripterygium wilfordii Hook f (TwHf), is effective in attenuating transplantation rejection and extending survival of cardiac xenografts...
2013: Journal of Translational Medicine
Laurent Leotoing, Fanny Chereau, Silvère Baron, Florent Hube, Hugo J Valencia, Didier Bordereaux, Jeroen A Demmers, John Strouboulis, Véronique Baud
NF-κB transcription factors are pivotal players in controlling inflammatory and immune responses, as well as cell proliferation and apoptosis. Aberrant regulation of NF-κB and the signaling pathways that regulate its activity have been involved in various pathologies, particularly cancers, as well as inflammatory and autoimmune diseases. NF-κB activation is tightly regulated by the IκB kinase (IKK) complex, which is composed of two catalytic subunits IKKα and IKKβ, and a regulatory subunit IKKγ/NEMO...
September 16, 2011: Journal of Biological Chemistry
C Scielzo, B Apollonio, L Scarfò, A Janus, M Muzio, E Ten Hacken, P Ghia, F Caligaris-Cappio
Malignant B lymphocytes from chronic lymphocytic leukemia (CLL) patients maintain the capacity to respond to CD40 ligation, among other microenvironmental stimuli. In this study, we show that (i) leukemic CLL cells stimulated with the soluble form of CD40L in vitro show differential responses in terms of upregulation of surface markers (CD95 and CD80) and induction of chemokines (CCL22 and CCL17) expression/secretion, and that (ii) these changes are mirrored by a distinct activation of intracellular signalling pathways including increase in IKKalpha/beta phosphorylation and upregulation of antiapoptotic proteins (BCL-2 and MCL-1)...
November 2011: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Tomoyuki Tsumuraya, Chie Ishikawa, Yoshiaki Machijima, Sawako Nakachi, Masachika Senba, Junichi Tanaka, Naoki Mori
We evaluated the anti-adult T-cell leukemia (ATL) effects of hippuristanol, an eukaryotic translation initiation inhibitor from the coral Isis hippuris. Hippuristanol inhibited proliferation of HTLV-1-infected T-cell lines and ATL cells, but not normal peripheral blood mononuclear cells. It induced cell cycle arrest during G₁ phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and induced apoptosis by reducing the expression of Bcl-x(L), c-IAP2, XIAP and c-FLIP. The induced apoptosis was associated with activation of caspase-3, -8 and -9...
March 15, 2011: Biochemical Pharmacology
Wenchang Zhao, Lijun Song, Deng Hongzhu
Sulfasalazine salicylazosulfapyridine (SASP), consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, is an effective drug in the treatment of inflammatory bowel diseases (IBD). However, its mechanism of action remains a matter of debate. The objective of our work was to investigate SASP's effect on NF-kappaB signal transduction pathway in transcriptional regulation level. Repeated colitis was induced by administration of 4 cycles of 4% dextran sulfate sodium (DSS); The severity of colitis was assessed on the basis of clinical signs, colon length, and histology scores...
September 2010: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Romina S Ilad, Steven D Fleming, Christopher R Murphy, Asgerally T Fazleabas
The aim of the present study was to conduct a semiquantitative immunohistochemical investigation into the levels of intermediary proteins within the nuclear factor (NF)-kappaB pathway throughout the menstrual cycle in a non-human primate, namely the baboon (Papio anubis), with and without endometriosis. Formalin-fixed eutopic (n = 2-4) and ectopic (n = 6-7) endometrial tissues from baboons at the mid-luteal phase were embedded in paraffin and examined for NF-kappaB pathway components (i.e. IkappaB kinase (IKK) alpha, IKKbeta, phosphorylated (phospho-) IkappaBalpha and phospho-NF-kappaB p65 subunit), ubiquitin, 19S proteasome and the NF-kappaB activator tumour necrosis factor (TNF)-alpha...
2010: Reproduction, Fertility, and Development
Jiaxi Song, Junping Kou, Yalin Huang, Boyang Yu
Our previous results suggested that ruscogenin inhibited tumor necrosis factor alpha (TNF-alpha)-induced leukocyte adhesion, which correlated with its suppression of intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells. In the present studies, we further examined its effects on the main signaling pathways involved in upregulation of ICAM-1 induced by TNF-alpha in human umbilical vein endothelial cells (HUVECs). The results showed that ruscogenin significantly suppressed p65 phosphorylation, IkappaB-alpha phosphorylation and degradation, and inhibited IkappaB kinase alpha (IKKalpha) and IKKbeta activation induced by TNF-alpha...
2010: Journal of Pharmacological Sciences
Tao Li, Michael J Morgan, Swati Choksi, Yan Zhang, You-Sun Kim, Zheng-gang Liu
MicroRNAs are key regulators of many biological processes, including cell differentiation. Here we show that during human monocyte-macrophage differentiation, expression of the microRNAs miR-223, miR-15a and miR-16 decreased considerably, which led to higher expression of the serine-threonine kinase IKKalpha in macrophages. In macrophages, higher IKKalpha expression in conjunction with stabilization of the kinase NIK induced larger amounts of p52. Because of low expression of the transcription factor RelB in untreated macrophages, high p52 expression repressed basal transcription of both canonical and noncanonical NF-kappaB target genes...
September 2010: Nature Immunology
Xiao-Guang Gong, Yun-Fu Lv, Xin-Qiu Li, Fu-Guo Xu, Qing-Yong Ma
Pancreatic cancer is the fourth leading cause of cancer-related death in the western countries and it is resistant to almost all cytotoxic drugs. In the current study, we explored the gemcitabine resistance induced by the interaction between Annexin A2 (ANXA2) and alternatively spliced segment of tenascin-C (TNfnA-D). In the pancreatic cancer cell culture system in vitro, it was proved that exogenous recombinant TNfnA-D combined with the cell surface ANXA2 specifically and their interaction suppressed gemcitabine-induced cytotoxicity on pancreatic cancer cells in a dose-dependent manner...
2010: Biological & Pharmaceutical Bulletin
Yoon-Jae Song, Myung-Soo Kang
Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1)-induced NF-kappaB activation is essential for EBV-transformed B cell survival. LMP1 has two C-terminal cytoplasmic domains referred to as C-Terminal Activation Regions (CTAR) 1 and 2 that activate the alternative and canonical NF-kappaB pathways, respectively. While CTAR2 activates TRAF6, IKKbeta and IKKgamma-dependent canonical NF-kappaB pathway, CTAR1 interacts with TRAF2 and TRAF3 and activates NIK and IKKalpha-dependent alternative NF-kappaB pathway involving p100 processing into functional p52...
October 2010: Virus Genes
Isra Darwech, Jesse E Otero, Muhammad A Alhawagri, Yousef Abu-Amer
The transcription factor NF-kappaB is crucial for numerous cellular functions such as survival, differentiation, immunity, and inflammation. A key function of this family of transcription factors is regulation of osteoclast differentiation and function, which in turn controls skeletal homeostasis. The IkappaB kinase (IKK) complex, which contains IKKalpha, IKKbeta, and IKKgamma, is required for activation of NF-kappaB, and deletion of either IKKalpha or IKKbeta resulted with defective osteoclast differentiation and survival...
August 13, 2010: Journal of Biological Chemistry
Ida Grotterød, Gunhild M Maelandsmo, Kjetil Boye
BACKGROUND: The metastasis-promoting protein S100A4 activates the transcription factor NF-kappaB through the classical NF-kappaB activation pathway. The upstream signal transduction mechanisms leading to increased NF-kappaB activity are, however, incompletely characterized. METHODS: The human osteosarcoma cell line II-11b was stimulated with recombinant S100A4 in the presence or absence of inhibitors of common signal transduction pathways, and NF-kappaB activity was examined using a luciferase-based reporter assay and phosphorylation of IkappaBalpha...
2010: BMC Cancer
Chin-Jung Hsu, Tsang-Yu Lin, Chien-Chung Kuo, Chun-Hao Tsai, Mou-Zen Lin, Horng-Chaung Hsu, Yi-Chin Fong, Chih-Hsin Tang
Invasion of tumor cells is the primary cause of therapeutic failure in malignant chondrosarcomas treatment. Receptor activator of nuclear factor-kappaB ligand (RANKL) and its receptor, RANK, play a key roles in osteoclastogenesis and tumor metastasis. We found that the RANKL and RANK expression in human chondrosarcoma tissues was higher than that in normal cartilage. We also found that RANKL directed the migration and increased cell surface expression of beta1 integrin in human chondrosarcoma cells (JJ012 cells)...
September 1, 2010: Journal of Cellular Biochemistry
Bahram Razani, Brian Zarnegar, A Jimmy Ytterberg, Travis Shiba, Paul W Dempsey, Carl F Ware, Joseph A Loo, Genhong Cheng
Canonical and noncanonical nuclear factor kappaB (NF-kappaB) signaling are the two basic pathways responsible for the release of NF-kappaB dimers from their inhibitors. Enhanced NF-kappaB signaling leads to inflammatory and proliferative diseases; thus, inhibitory pathways that limit its activity are critical. Whereas multiple negative feedback mechanisms control canonical NF-kappaB signaling, none has been identified for the noncanonical pathway. Here, we describe a mechanism of negative feedback control of noncanonical NF-kappaB signaling that attenuated the stabilization of NF-kappaB-inducing kinase (NIK), the central regulatory kinase of the noncanonical pathway, induced by B cell-activating factor receptor (BAFF-R) and lymphotoxin beta receptor (LTbetaR)...
2010: Science Signaling
Shao-Cong Sun
The noncanonical nuclear factor kappaB (NF-kappaB) pathway is a specific arm of NF-kappaB signaling that regulates important aspects of immune function. Activation of this pathway centers on the modulation of a pivotal signaling component: NF-kappaB-inducing kinase (NIK). Under normal conditions, NIK undergoes constitutive degradation, which keeps its abundance below the threshold required for its function, and signal-induced activation of the noncanonical NF-kappaB pathway is coupled with the stabilization and accumulation of NIK...
2010: Science Signaling
Sangwoon Chung, Isaac Kirubakaran Sundar, Hongwei Yao, Ye-Shih Ho, Irfan Rahman
Glutaredoxin 1 (Glrx1) is a small dithiol protein that regulates the cellular redox state and redox-dependent signaling pathways via modulation of protein glutathionylation. IkappaB kinase (IKK), an essential enzyme for NF-kappaB activation, can be subjected to S-glutathionylation leading to alteration of its activity. However, the role of Glrx1 in cigarette smoke (CS)-induced lung inflammation and chromatin modifications are not known. We hypothesized that Glrx1 regulates the CS-induced lung inflammation and chromatin modifications via differential regulation of IKKs by S-glutathionylation in mouse lung...
August 2010: American Journal of Physiology. Lung Cellular and Molecular Physiology
Wen Zhang, Xuan Zhang, Xiao-Li Wu, Liu-Sheng He, Xiao-Feng Zeng, Amrie C Crammer, Peter E Lipsky
OBJECTIVE: To investigate the role of TNF receptor-associated factor 2 (TRAF-2) and TRAF6 in CD40-induced nuclear factor-kappaB (NF-kappaB) signaling pathway and whether CD40 signaling requires TRAF2. METHODS: Human B cell lines were transfected with plasmids expressing wild type TRAF2 or dominant negative TRAF2, TRAF2-shRNA, or TRAF6-shRNA. The activation of NF-kappaB was detected by Western blot, kinase assay, transfactor enzyme-linked immunosorbent assay (ELISA), and fluorescence resonance energy transfer (FRET)...
March 2010: Chinese Medical Sciences Journal, Chung-kuo i Hsüeh K'o Hsüeh Tsa Chih
Jun Cui, Liang Zhu, Xiaojun Xia, Helen Y Wang, Xavier Legras, Jun Hong, Jiabing Ji, Pingping Shen, Shu Zheng, Zhijian J Chen, Rong-Fu Wang
Stringent control of the NF-kappaB and type I interferon signaling pathways is critical to effective host immune responses, yet the molecular mechanisms that negatively regulate these pathways are poorly understood. Here, we show that NLRC5, a member of the highly conserved NOD-like protein family, can inhibit the IKK complex and RIG-I/MDA5 function. NLRC5 inhibited NF-kappaB-dependent responses by interacting with IKKalpha and IKKbeta and blocking their phosphorylation. It also interacted with RIG-I and MDA5, but not with MAVS, to inhibit RLR-mediated type I interferon responses...
April 30, 2010: Cell
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