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https://www.readbyqxmd.com/read/28075192/loss-of-monocyte-chemoattractant-protein-1-expression-delays-mammary-tumorigenesis-and-reduces-localized-inflammation-in-the-c3-1-sv40tag-triple-negative-breast-cancer-model
#1
Taryn L Cranford, Kandy T Velázquez, Reilly T Enos, Jackie E Bader, Meredith S Carson, Ioulia Chatzistamou, Mitzi Nagarkatti, E Angela Murphy
Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC...
January 11, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28072762/giving-axl-the-axe-targeting-axl-in-human-malignancy
#2
Carl M Gay, Kavitha Balaji, Lauren Averett Byers
The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers...
January 10, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28067670/mertk-receptor-cleavage-promotes-plaque-necrosis-and-defective-resolution-in-atherosclerosis
#3
Bishuang Cai, Edward B Thorp, Amanda C Doran, Brian E Sansbury, Mat J A P Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, Ira Tabas
Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance of apoptotic cells, or efferocytosis, by lesional macrophages, but the mechanisms underlying defective efferocytosis and its possible links to impaired resolution in atherosclerosis are incompletely understood. Here, we provide evidence that proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) reduces efferocytosis and promotes plaque necrosis and defective resolution...
January 9, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28049839/gas6-is-a-key-homeostatic-immunological-regulator-of-host-commensal-interactions-in-the-oral-mucosa
#4
Maria Nassar, Yaara Tabib, Tal Capucha, Gabriel Mizraji, Tsipora Nir, Meirav Pevsner-Fischer, Gili Zilberman-Schapira, Oded Heyman, Gabriel Nussbaum, Herve Bercovier, Asaf Wilensky, Eran Elinav, Tal Burstyn-Cohen, Avi-Hai Hovav
The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3-AXL-MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28035529/hereditary-retinal-dystrophy
#5
Thomas C Hohman
As our understanding of the genetic basis for inherited retinal disease has expanded, gene therapy has advanced into clinical development. When the gene mutations associated with inherited retinal dystrophies were identified, it became possible to create animal models in which individual gene were altered to match the human mutations. The retina of these animals were then characterized to assess whether the mutated genes produced retinal phenotypes characteristic of disease-affected patients. Following the identification of a subpopulation of patients with the affected gene and the development of techniques for the viral gene transduction of retinal cells, it has become possible to deliver a copy of the normal gene into the retinal sites of the mutated genes...
December 30, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28035396/anticancer-effect-of-luteolin-is-mediated-by-downregulation-of-tam-receptor-tyrosine-kinases-but-not-interleukin-8-in-non-small-cell-lung-cancer-cells
#6
Youn Ju Lee, Taeho Lim, Min Su Han, Sun-Hwa Lee, Suk-Hwan Baek, Hong-Yan Nan, Chuhee Lee
TAM receptor tyrosine kinases (RTKs), Tyro3, Axl and MerTK, transduce diverse signals responsible for cell survival, growth, proliferation and anti-apoptosis. In the present study, we demonstrated the effect of luteolin, a flavonoid with antioxidant, anti-inflammatory and anticancer activities, on the expression and activation of TAM RTKs and the association with its cytotoxicity in non-small cell lung cancer (NSCLC) cells. We observed the cytotoxic effect of luteolin in parental A549 and H460 cells as well as in cisplatin-resistant A549/CisR and H460/CisR cells...
February 2017: Oncology Reports
https://www.readbyqxmd.com/read/28034848/regulated-intramembrane-proteolysis-of-the-axl-receptor-kinase-generates-an-intracellular-domain-that-localizes-in-the-nucleus-of-cancer-cells
#7
Yinzhong Lu, Jun Wan, Zhifeng Yang, Xiling Lei, Qi Niu, Lanxin Jiang, Willemijn M Passtoors, Aiping Zang, Patrick C Fraering, Fang Wu
Deregulation of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases (RTKs) has recently been demonstrated to predominately promote survival and chemoresistance of cancer cells. Intramembrane proteolysis mediated by presenilin/γ-secretase is known to regulate the homeostasis of some RTKs. In the present study, we demonstrate that AXL, but not TYRO3 or MERTK, is efficiently and sequentially cleaved by α- and γ-secretases in various types of cancer cell lines. Proteolytic processing of AXL redirected signaling toward a secretase-mediated pathway, away from the classic, well-known, ligand-dependent canonical RTK signaling pathway...
December 29, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28032464/discovery-of-macrocyclic-pyrimidines-as-mertk-specific-inhibitors
#8
Andrew McIver, Weihe Zhang, Qingyang Liu, Xinpeng Jiang, Michael Stashko, James Nichols, Michael Miley, Jacqueline Norris-Drouin, Mischa Machius, Deborah DeRyckere, Edgar Wood, Douglas Graham, H Shelton Earp, Dmitri Kireev, Stephen Frye, Xiaodong Wang
Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinases inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this paper, we have successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in a 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK...
December 28, 2016: ChemMedChem
https://www.readbyqxmd.com/read/28003382/mek1-2-inhibition-promotes-macrophage-reparative-properties
#9
Matthew E Long, William E Eddy, Ke-Qin Gong, Lara L Lovelace-Macon, Ryan S McMahan, Jean Charron, W Conrad Liles, Anne M Manicone
Macrophages have important functional roles in regulating the timely promotion and resolution of inflammation. Although many of the intracellular signaling pathways involved in the proinflammatory responses of macrophages are well characterized, the components that regulate macrophage reparative properties are less well understood. We identified the MEK1/2 pathway as a key regulator of macrophage reparative properties. Pharmacological inhibition of the MEK1/2 pathway by a MEK1/2 inhibitor (MEKi) significantly increased expression of IL-4/IL-13 (M2)-responsive genes in murine bone marrow-derived and alveolar macrophages...
January 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27994735/design-and-synthesis-of-novel-macrocyclic-mer-tyrosine-kinase-inhibitors
#10
Xiaodong Wang, Jing Liu, Weihe Zhang, Michael A Stashko, James Nichols, Michael J Miley, Jacqueline Norris-Drouin, Zhilong Chen, Mischa Machius, Deborah DeRyckere, Edgar Wood, Douglas K Graham, H Shelton Earp, Dmitri Kireev, Stephen V Frye
Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC50 below 40 nM in a cell-based MerTK phosphor-protein ELISA assay...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27958361/deficiency-of-axl-in-bone-marrow-derived-cells-does-not-affect-advanced-atherosclerotic-lesion-progression
#11
Manikandan Subramanian, Jonathan D Proto, Glenn K Matsushima, Ira Tabas
AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl(-/-) or wild-type mice were transplanted into lethally irradiated Ldlr(-/-) mice...
December 13, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27916840/ligand-activation-of-tam-family-receptors-implications-for-tumor-biology-and-therapeutic-response
#12
REVIEW
Viralkumar Davra, Stanley G Kimani, David Calianese, Raymond B Birge
The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor clinical outcomes. In recent years, there has been great interest in the study of TAM receptors in cancer, stemming both from their roles as oncogenic signaling receptors, as well as their roles in tumor immunology...
November 29, 2016: Cancers
https://www.readbyqxmd.com/read/27895032/molecular-pathways-receptor-ectodomain-shedding-in-treatment-resistance-and-monitoring-of-cancer
#13
Miles A Miller, Ryan J Sullivan, Douglas A Lauffenburger
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently over-expressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL-6R; the Notch receptors; type-I and -III TGF-β receptors; receptor tyrosine kinases (RTKs) such as HER2, HER4, and VEGFR2; and in particular, MET and TAM-family RTKs AXL and Mer (MerTK)...
November 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27875314/receptor-mer-tyrosine-kinase-proto-oncogene-mertk-is-not-required-for-transfer-of-bis-retinoids-to-the-retinal-pigmented-epithelium
#14
Grazyna Palczewska, Akiko Maeda, Marcin Golczak, Eisuke Arai, Zhiqian Dong, Lindsay Perusek, Brian Kevany, Krzysztof Palczewski
Accumulation of bis-retinoids in the retinal pigmented epithelium (RPE) is a hallmark of aging and retinal disorders such as Stargardt disease and age-related macular degeneration. These aberrant fluorescent condensation products, including di-retinoid-pyridinium-ethanolamine (A2E), are thought to be transferred to RPE cells primarily through phagocytosis of the photoreceptor outer segments. However, we observed by two-photon microscopy that mouse retinas incapable of phagocytosis due to a deficiency of the c-Mer proto-oncogene tyrosine kinase (Mertk) nonetheless contained fluorescent retinoid condensation material in their RPE...
December 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27865593/identification-of-novel-therapeutic-targets-in-anaplastic-thyroid-carcinoma-using-functional-genomic-mrna-profiling-paving-the-way-for-new-avenues
#15
Pascal K C Jonker, Gooitzen M van Dam, Sjoukje F Oosting, Schelto Kruijff, Rudolf S N Fehrmann
BACKGROUND: Currently, anaplastic thyroid carcinoma has a very poor prognosis and there is an unmet need for new therapeutic options. Therefore, this study aims to identify upregulated genes in anaplastic thyroid carcinoma with known drug interactions that could serve as new therapeutic targets. METHODS: Publicly available microarray expression profiles of anaplastic thyroid carcinoma and normal thyroid tissue were collected. FGmRNA-profiling was applied, which is a recently developed method that enhances the ability to capture the downstream effects of genomic alterations on gene expression levels...
January 2017: Surgery
https://www.readbyqxmd.com/read/27863506/interleukin-37-limits-monosodium-urate-crystal-induced-innate-immune-responses-in-human-and-murine-models-of-gout
#16
Lei Liu, Yu Xue, Yingfeng Zhu, Dandan Xuan, Xue Yang, Minrui Liang, Juan Wang, Xiaoxia Zhu, Jiong Zhang, Hejian Zou
BACKGROUND: Interleukin (IL)-37 has emerged as a fundamental inhibitor of innate immunity. Acute gout is a self-limiting inflammatory response to monosodium urate (MSU) crystals. In the current study, we assessed the preventive and therapeutic effect of recombinant human IL-37 (rhIL-37) in human and murine gout models. METHODS: We investigated the expression of IL-37 in patients with active and inactive gouty arthritis and assessed the effect of rhIL-37 in human and murine gout models: a human monocyte cell line (THP-1) and human synovial cells (containing macrophage-like and fibroblast-like synoviocytes) exposed to MSU crystals, a peritoneal murine model of gout and a murine gouty arthritis model...
November 18, 2016: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/27834816/targeting-the-tam-receptors-in-leukemia
#17
REVIEW
Madeline G Huey, Katherine A Minson, H Shelton Earp, Deborah DeRyckere, Douglas K Graham
Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma...
November 8, 2016: Cancers
https://www.readbyqxmd.com/read/27827458/microrna-126-overexpression-rescues-diabetes-induced-impairment-in-efferocytosis-of-apoptotic-cardiomyocytes
#18
Sahana Suresh Babu, Rajarajan A Thandavarayan, Darukeshwara Joladarashi, Prince Jeyabal, Shashirekha Krishnamurthy, Arvind Bhimaraj, Keith A Youker, Prasanna Krishnamurthy
Efferocytosis, a process of clearance of apoptotic cells by phagocytes, is essential for successful resolution of inflammation and maintenance of tissue homeostasis. Diabetes compromises the function of macrophages leading to adverse inflammatory response during wound healing, myocardial injury, atherosclerosis and autoimmune disorders. However, the effect of diabetes on macrophage-mediated efferocytosis of apoptotic cardiomyocytes (ACM) and the molecular mechanisms involved are not understood so far. In the present study we found that invitro efferocytosis of ACM was impaired in macrophages from db/db (diabetic) mice...
November 9, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27801848/the-gas6-tam-system-and-multiple-sclerosis
#19
REVIEW
Mattia Bellan, Mario Pirisi, Pier Paolo Sainaghi
Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the biological actions of which are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, collectively named TAM. Over the last few decades, many progresses have been done in the understanding of the biological activities of this highly pleiotropic system, which plays a role in the regulation of immune response, inflammation, coagulation, cell growth, and clearance of apoptotic bodies. Recent findings have further related Gas6 and TAM receptors to neuroinflammation in general and, specifically, to multiple sclerosis (MS)...
October 28, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27788572/gm-csf-grown-bone-marrow-derived-cells-are-composed-of-phenotypically-different-dendritic-cells-and-macrophages
#20
Yi Rang Na, Daun Jung, Gyo Jeong Gu, Seung Hyeok Seok
Granulocyte-macrophage colony stimulating factor (GM-CSF) has a role in inducing emergency hematopoiesis upon exposure to inflammatory stimuli. Although GM-CSF generated murine bone marrow derived cells have been widely used as macrophages or dendritic cells in research, the exact characteristics of each cell population have not yet been defined. Here we discriminated GM-CSF grown bone marrow derived macrophages (GM-BMMs) from dendritic cells (GM-BMDCs) in several criteria. After C57BL/6J mice bone marrow cell culture for 7 days with GM-CSF supplementation, two main populations were observed in the attached cells based on MHCII and F4/80 marker expressions...
October 2016: Molecules and Cells
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