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Tzeng T.-C.,Autoimmunity and Inflammation Program | Tzeng T.-C.,Cornell University | Chyou S.,Autoimmunity and Inflammation Program | Tian S.,Autoimmunity and Inflammation Program | And 7 more authors.
Journal of Immunology | Year: 2010

Lymph node expansion during immune responses is accompanied by rapid vascular expansion. The re-establishment of quiescence and stabilization of the newly expanded vasculature and the regulatory mechanisms involved have not been well studied. We show that although initiation of vascular expansion in immune-stimulated nodes is associated with upregulated endothelial cell proliferation, increased high endothelial venule trafficking efficiency and VCAM-1 expression, and disrupted perivascular fibroblastic reticular cell organization, the re-establishment of vascular quiescence and stabilization postexpansion is characterized by reversal of these phenomena. Although CD11cmed cells are associated with the initiation of vascular expansion, CD11chiMHC class II (MHC II)med dendritic cells (DCs) accumulate later, and their short-term depletion in mice abrogates the re-establishment of vascular quiescence and stabilization. CD11chiMHC IImed cells promote endothelial cell quiescence in vitro and, in vivo, mediate quiescence at least in part by mediating reduced lymph node vascular endothelial growth factor. Disrupted vascular quiescence and stabilization in expanded nodes is associated with attenuated T cell-dependent B cell responses. These results describe a novel mechanism whereby CD11c hiMHC IImed DCs regulate the re-establishment of vascular quiescence and stabilization after lymph node vascular expansion and suggest that these DCs function in part to orchestrate the microenvironmental alterations required for successful immunity. Copyright © 2010 by The American Association of Immunologists, Inc.


Godin J.,University of Liege | Thomas N.,University of Liege | Laguesse S.,University of Liege | Malinouskaya L.,University of Liege | And 13 more authors.
Developmental Cell | Year: 2012

The migration of cortical interneurons is characterized by extensive morphological changes that result from successive cycles of nucleokinesis and neurite branching. Their molecular bases remain elusive, and the present work describes how p27Kip1 controls cell-cycle-unrelated signaling pathways to regulate these morphological remodelings. Live imaging reveals that interneurons lacking p27Kip1 show delayed tangential migration resulting from defects in both nucleokinesis and dynamic branching of the leading process. At the molecular level, p27Kip1 is a microtubule-associated protein that promotes polymerization of microtubules in extending neurites, thereby contributing to tangential migration. Furthermore, we show that p27Kip1 controls actomyosin contractions that drive both forward translocation of the nucleus and growth cone splitting. Thus, p27Kip1 cell-autonomously controls nucleokinesis and neurite branching by regulating both actin and microtubule cytoskeletons.


Evelyn C.R.,Childrens Hospital Research Foundation | Duan X.,Childrens Hospital Research Foundation | Biesiada J.,Childrens Hospital Research Foundation | Seibel W.L.,Childrens Hospital Research Foundation | And 3 more authors.
Chemistry and Biology | Year: 2014

Summary Ras GTPases regulate intracellular signaling involved in cell proliferation. Elevated Ras signaling activity has been associated with human cancers. Ras activation is catalyzed by guanine nucleotide exchange factors (GEFs), of which SOS1 is a major member that transduces receptor tyrosine kinase signaling to Ras. We have developed a rational approach coupling virtual screening with experimental screening in identifying small-molecule inhibitors targeting the catalytic site of SOS1 and SOS1-regulated Ras activity. A lead inhibitor, NSC-658497, was found to bind to SOS1, competitively suppress SOS1-Ras interaction, and dose-dependently inhibit SOS1 GEF activity. Mutagenesis and structure-activity relationship studies map the NSC-658497 site of action to the SOS1 catalytic site, and define the chemical moieties in the inhibitor essential for the activity. NSC-658497 showed dose-dependent efficacy in inhibiting Ras, downstream signaling activities, and associated cell proliferation. These studies establish a proof of principle for rational design of small-molecule inhibitors targeting Ras GEF enzymatic activity. ©2014 Elsevier Ltd. All rights reserved.


Plageman Jr. T.F.,United Medical Systems | Plageman Jr. T.F.,Childrens Hospital Research Foundation | Chung M.-I.,University of Texas at Austin | Lou M.,Lamar University | And 8 more authors.
Development | Year: 2010

Embryonic development requires a complex series of relative cellular movements and shape changes that are generally referred to as morphogenesis. Although some of the mechanisms underlying morphogenesis have been identified, the process is still poorly understood. Here, we address mechanisms of epithelial morphogenesis using the vertebrate lens as a model system. We show that the apical constriction of lens epithelial cells that accompanies invagination of the lens placode is dependent on Shroom3, a molecule previously associated with apical constriction during morphogenesis of the neural plate. We show that Shroom3 is required for the apical localization of F-actin and myosin II, both crucial components of the contractile complexes required for apical constriction, and for the apical localization of Vasp, a Mena family protein with F-actin anti-capping function that is also required for morphogenesis. Finally, we show that the expression of Shroom3 is dependent on the crucial lens-induction transcription factor Pax6. This provides a previously missing link between lens-induction pathways and the morphogenesis machinery and partly explains the absence of lens morphogenesis in Pax6-deficient mutants. © 2010. Published by The Company of Biologists Ltd.


McLendon P.M.,Childrens Hospital Research Foundation | Robbins J.,Childrens Hospital Research Foundation
Circulation Research | Year: 2015

Baseline physiological function of The mammalian heart is under The constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally, and this depends on them assuming and maintaining proper conformation. This review explores The multiple defenses a cell may use for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in The face of normal or pathological stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In The absence of these corrective processes, they may become toxic to The cell. Herein, we explore some of The underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes because these misfolded proteins can lead to aggregation or The formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of The cell's ability to maintain protein homeostasis. Some underlying mechanisms are discussed and The therapeutic potential of interfering with proteotoxicity in The heart is explored. © 2015 American Heart Association, Inc.

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