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Wu X.,New York University | Gong S.,Arthritis and Tissue Degeneration Program | Gong S.,Rockefeller University | Roy-Burman P.,University of Southern California | And 2 more authors.
Endocrine-Related Cancer | Year: 2013

Mouse models of prostate cancer (PCa) are critical for understanding the biology of PCa initiation, progression, and treatment modalities. Here, we summarize recent advances in PCa mouse models that led to new insights into specific gene functions in PCa. For example, the study of transgenic mice with TMPRSS2/ERG, an androgen-regulated fusion protein, revealed its role in developing PCa precursor lesions, prostate intraepithelial neoplasia; however, it is not sufficient for PCa development. Double deficiency of Pten and Smad4 leads to a high incidence of metastatic PCa. Targeted deletion of Pten in castration-resistant Nkx3-1-expressing cells results in rapid carcinoma formation after androgen-mediated regeneration, indicating that progenitor cells with luminal characteristics can play a role in initiation of PCa. Transgenic mice with activated oncogenes, growth factors, and steroid hormone receptors or inactivated tumor suppressors continue to provide insights into disease progression from initiation to metastasis. Further development of new PCa models with spatial and temporal regulation of candidate gene expression will probably enhance our understanding of the complex events that lead to PCa initiation and progression, thereby invoking novel strategies to combat this common disease in men. © 2013 Society for Endocrinology Published by Bioscientifica Ltd. Source


Kelly E.K.,Graduate Program in Cell Biology and Genetics | Wang L.,Arthritis and Tissue Degeneration Program | Ivashkiv L.B.,Graduate Program in Immunology and Microbial Pathogenesis
Journal of Immunology | Year: 2010

Outside of the TLR paradigm, there is little understanding of how pathogen recognition at the cell surface is linked to functional responses in cells of the innate immune system. Recent work in this area demonstrates that the yeast particle zymosan, by binding to the β-glucan receptor Dectin-1, activates an ITAM-Syk - dependent pathway in dendritic cells, which is required for optimal cytokine production and generation of an oxidative burst. It remains unclear how activation of Syk is coupled to effector mechanisms. In human macrophages, zymosan rapidly activated a calcium-dependent pathway downstream of Dectin-1 and Syk that led to activation of calmodulin-dependent kinase II and Pyk2. Calmodulin-dependent kinase and Pyk2 transduced calcium signals into activation of the ERK - MAPK pathway, CREB, and generation of an oxidative burst, leading to downstream production of IL-10. These observations identify a new calcium-mediated signaling pathway activated by zymosan and link this pathway to both inflammatory and anti-inflammatory responses in macrophages. Copyright © 2010 by The American Association of Immunologists, Inc. Source


Maretzky T.,Arthritis and Tissue Degeneration Program | Blobel C.P.,New York University | Guaiquil V.,Cornell University
Investigative ophthalmology & visual science | Year: 2014

PURPOSE: Retinal neovascularization is found in diseases such as macular degeneration, diabetic retinopathy, or retinopathy of prematurity and is usually caused by alterations in oxygen supply. We have previously described that mice lacking the membrane-anchored metalloproteinase ADAM15 (a Disintegrin and Metalloprotease 15) have decreased pathological neovascularization of the retina in the oxygen-induced retinopathy (OIR) model. The main purpose of the present study was to determine the contribution of the catalytic activity of ADAM15 to OIR.METHODS: To address this question, we generated knock-in mice carrying an inactivating Glutamate to Alanine (E>A) point mutation in the catalytic site of ADAM15 (Adam15E>A mice) and subjected these animals to the OIR model and a heterotopic tumor model. Moreover, we used cell-based assays to determine whether ADAM15 can process cell surface receptors involved in angiogenesis.RESULTS: We found that pathological neovascularization in the OIR model in Adam15E>A mice was comparable to that observed in wild type mice, but tumor implantation by heterotopically injected melanoma cells was reduced. In cell-based assays, overexpressed ADAM15 could process the FGFR2iiib, but was unable to process several receptors with roles in angiogenesis.CONCLUSIONS: Collectively, these results suggest that the catalytic activity of ADAM15 is not crucial for its function in promoting pathological neovascularization in the mouse OIR model, most likely because of the very limited substrate repertoire of ADAM15. Instead, other noncatalytic functions of ADAM15 must be important for its role in the OIR model. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. Source


Antoniv T.T.,Arthritis and Tissue Degeneration Program | Ivashkiv L.B.,Arthritis and Tissue Degeneration Program | Ivashkiv L.B.,Cornell University
Immunology | Year: 2011

Interleukin-10 (IL-10) is an immunosuppressive cytokine that inhibits inflammatory gene expression. Phosphatidylinositol 3-kinase (PI3K) -mediated signalling regulates inflammatory responses and can induce IL-10 production, but a role for PI3K signalling in cellular responses to IL-10 is not known. In this study we investigated the involvement of the PI3K-Akt-GSK3 signalling pathway in IL-10-induced gene expression and IL-10-mediated suppression of Toll-like receptor-induced gene expression in primary human macrophages. A combination of loss and gain of function approaches using kinase inhibitors, expression of constitutively active Akt, and RNA interference in primary human macrophages showed that expression of a subset of IL-10-inducible genes was dependent on PI3K-Akt signalling. The effects of PI3K-Akt signalling on IL-10 responses were mediated at least in part by glycogen synthase kinase 3 (GSK3). In accordance with a functional role for PI3K pathways in contributing to the suppressive actions of IL-10, PI3K signalling augmented IL-10-mediated inhibition of lipopolysaccharide-induced IL-1, IL-8 and cyclo-oxygenase-2 expression. The PI3K signalling selectively modulated IL-10 responses, as it was not required for inhibition of tumour necrosis factor expression or for induction of certain IL-10-inducible genes such as SOCS3. These findings identify a new mechanism by which PI3K-mediated signalling can suppress inflammation by regulating IL-10-mediated gene induction and anti-inflammatory function. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd. Source


Yarilina A.,Arthritis and Tissue Degeneration Program | Ivashkiv L.B.,Arthritis and Tissue Degeneration Program | Ivashkiv L.B.,Cornell University
Current Directions in Autoimmunity | Year: 2010

TNF and type I interferons (IFNs) are induced by microbial stimuli and mediate innate immune responses. They are also involved in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Activated macrophages are an important driving force of inflammatory reactions and one of the major producers of TNF in innate immunity and chronic inflammation. Despite the fact that cells at sites of damage are continuously exposed to both cytokines, little is known about mechanisms regulating TNF and type I IFN interactions during inflammation. In this review, we discuss the role of an IFN-β-mediated autocrine loop in the regulation of gene expression program induced by TNF in myeloid cells. © 2010 S. Karger AG, Basel. Source

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