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Research Publications

"The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting"

TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-B (NF-B) pathway.

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Molecular and Structural Basis of Cytokine Receptor Pleiotropy in the Interleukin-4/13 System

Sherry L. LaPorte, Z. Sean Juo, Jana Vaclavikova, Leremy A. Colf, Xiulan Qi, Nicola M. Heller, Achsah D. Keegan and K. Christopher Garcia

Interleukin-4 and Interleukin-13 are cytokines critical to the development of T cell-mediated humoral immune responses, which are associated with allergy and asthma, and exert their actions through three different combinations of shared receptors.

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Spatially distinct production of reactive oxygen species regulates platelet activation

Nadia Bakdash, Mark S. Williams

Platelets play a key role in hemostasis and changes in redox balance are known to alter platelet activation and aggregation. Interestingly, activation of platelets leads to production of reactive oxygen species (ROS), but the role(s) of these ROS remain unclear. Using flow cytometry and chemiluminescence, agonist-induced ROS generation was found to be spatially distinct with stimulation through the major collagen receptor GPVI inducing only intraplatelet ROS while thrombin induced production of extracellular ROS.

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Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditions.

Yang Y, Bai J, Shen R, Brown SA, Komissarova E, Huang Y, Jiang N, Alberts GF, Costa M, Lu L, Winkles JA, Dai W.

Polo-like kinase 3 (Plk3) is an important mediator of the cellular responses to genotoxic stresses. In this study, we examined the physiologic function of Plk3 by generating Plk3-deficient mice. Plk3(-/-) mice displayed an increase in weight and developed tumors in various organs at advanced age. Many tumors in Plk3(-/-) mice were large in size, exhibiting enhanced angiogenesis.

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SerpinB2 protection of retinoblastoma protein from calpain enhances tumor cell survival.

Tonnetti L, Netzel-Arnett S, Darnell GA, Hayes T, Buzza MS, Anglin IE, Suhrbier A, Antalis TM

The tumor suppressor retinoblastoma protein (Rb) plays a pivotal role in the regulation of cell proliferation and sensitivity to apoptosis through binding to E2F transcription factors. Loss of Rb in response to genotoxic stress or inflammatory cytokines can enhance cell death, in part, by eliminating Rb-mediated repression of proapoptotic gene transcription. Here we show that calpain cleavage of Rb facilitates Rb loss by proteasome degradation and that this may occur during tumor necrosis factor alpha-induced apoptosis.

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Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability.

Anna. P. Lillis, Irina. Mikhailenko and Dudley. K. Strickland

The low-density lipoprotein (LDL) receptor related protein (LRP1 or LRP) is a large endocytic receptor widely expressed in several tissues and known to play roles in areas as diverse as lipoprotein metabolism, degradation of proteases, activation of lysosomal enzymes and cellular entry of bacterial toxins and viruses.

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Soluble Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Overexpression in HEK293 Cells Promotes Tumor Growth and Angiogenesis in Athymic Nude Mice

David H. Ho, Hong Vu, Sharron A. N. Brown, Patrick J. Donohue, Heather N. Hanscom and Jeffrey A. Winkles

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of structurally related cytokines. TWEAK acts on responsive cells via binding to a cell surface receptor named Fn14. Recent studies have demonstrated that TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production.

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Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration.

Chunzhang Cao, Daniel A Lawrence, Yang Li, Christine A F Von Arnim, Joachim Herz, Enming J Su, Alexandra Makarova, Bradley T Hyman, Dudley K Strickland and Li Zhang

Migration of activated macrophages is essential for resolution of acute inflammation and the initiation of adaptive immunity. Here, we show that efficient macrophage migration in inflammatory environment depends on Mac-1 recognition of a binary complex consisting of fibrin within the provisional matrix and the protease tPA (tissue-type plasminogen activator).

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The GATA factor Serpent cross-regulates lozenge and u-shaped expression during Drosophila blood cell development.

Selen Muratoglu, Barry Hough, Soe T. Mon and Nancy Fossett

The Drosophila GATA factor Serpent interacts with the RUNX factor Lozenge to activate the crystal cell program, whereas SerpentNC binds the Friend of GATA protein U-shaped to limit crystal cell production. Here, we identified a lozenge minimal hematopoietic cis-regulatory module and showed that lozenge-lacZ reporter-gene expression was autoregulated by Serpent and Lozenge.

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A specific role of integrin Mac-1 in accelerated macrophage efflux to the lymphatics.

Chunzhang Cao, Daniel A. Lawrence, Dudley K. Strickland, and Li Zhang

In response to injury, monocytes migrate to the site of inflammation, where they differentiate into macrophages and participate in various biologic processes. However, their fate during the resolution of acute inflammation is not fully understood. Here, we show that inflammatory macrophages do not die locally by apoptosis; rather, they migrate across the peritoneal mesothelium to the lymphatics, through which they further migrate to the lymph nodes and to the blood circulation.

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Regulation of Drosophila Friend of GATA gene, u-shaped, during hematopoiesis: A direct role for Serpent and Lozenge.

Selen Muratoglu, Betsy Garratt, Kristy Hyman, Kathleen Gajewski, Robert A. Schulz and Nancy Fossett

Friend of GATA proteins interact with GATA factors to regulate development in a variety of tissues. We analyzed cis- and trans-regulation of the Drosophila gene, u-shaped, to better understand the transcriptional control of this important gene family during hematopoiesis. Using overlapping genomic fragments driving tissue-specific reporter-gene (lacZ) expression, we identified two minimal hematopoietic enhancers within the 7.4 kb region upstream of the transcription start site.

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Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP.

Jaeyul Kwon, Cheng-Kui Qu, Jin-Soo Maeng, Rustom Falahati, Chunghee Lee, and Mark S Williams

Receptor-stimulated generation of intracellular reactive oxygen species (ROS) modulates signal transduction, although the mechanism(s) is unclear. One potential basis is the reversible oxidation of the active site cysteine of protein tyrosine phosphatases (PTPs). Here, we show that activation of the antigen receptor of T cells (TCR), which induces production of ROS, induces transient inactivation of the SH2 domain-containing PTP, SHP-2, but not the homologous SHP-1.

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T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation.

Sharon H Jackson, Satish Devadas, Jaeyul Kwon, Ligia A Pinto and Mark S Williams

T cell receptor (TCR) stimulation induces rapid generation of reactive oxygen species, although the mechanisms for this are unclear. Here we found that T cells expressed a functional phagocyte-type nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. TCR crosslinking induced oxidase activation through the recruitment of preformed Fas ligand and Fas. TCR stimulation induced three separable events generating reactive oxygen species: