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‣ Via de sinalização do Sonic Hedgehog em leiomioma e leiomiossarcoma uterinos: estudo da expressão transcricional e protéica de moléculas envolvidas na via; Sonic Hedgehog signaling pathway in uterine leiomyoma and leiomyosarcoma: Protein and transcriptional expression study

Garcia, Natalia
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 03/02/2015 Português
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Leiomioma (LMU) e leiomiossarcoma (LMSU) são tumores mesenquimais que se desenvolvem no útero e apresentam comportamento clínico variável. Ambos são neoplasias do miométrio (MM), com mesmo padrão de diferenciação celular, porém com progressão clínica completamente diferente. Até o momento, existe grande controvérsia quanto aos fatores relacionados ao surgimento dessas neoplasias e uma possível malignização de um leiomioma pré-existente. Foi demonstrado que a ativação da via de sinalização do Sonic hedgehog (SHH) está relacionada ao desenvolvimento de diversos tipos de tumor, uma vez que a mesma desempenha importante papel na proliferação e diferenciação celular. O objetivo desse trabalho foi avaliar o padrão de expressão transcricional e protéica de moléculas envolvidas na via do SHH em LMU e LMSU. Foram avaliados a expressão de 106 genes, por PCR em tempo real, e de sete proteínas (SHH, PTCH 1, SMO, SUFU GLI 1-3 e HHIP 1), por imunoistoquímica, em 176 amostras (20 MM, 103 LMU - incluindo 16 leiomiomas não convencionais/LMA e 37 LMSU). Os resultados mostraram que a expressão gênica e protéica foram similares nas amostras de LMAU e LMSU. A expressão de AXIN 2, FZD 2, CCND 1, FZD 6, ESR 1 e IFT 52 foi associada com a sobrevida livre de doença; FZD3...

‣ Regulation of patched by sonic hedgehog in the developing neural tube.

Marigo, V; Tabin, C J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 03/09/1996 Português
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Ventral cell fates in the central nervous system are induced by Sonic hedgehog, a homolog of hedgehog, a secreted Drosophila protein. In the central nervous system, Sonic hedgehog has been identified as the signal inducing floor plate, motor neurons, and dopaminergic neurons. Sonic hedgehog is also involved in the induction of ventral cell type in the developing somites. ptc is a key gene in the Drosophila hedgehog signaling pathway where it is involved in transducing the hedgehog signal and is also a transcriptional target of the signal. PTC, a vertebrate homolog of this Drosophila gene, is genetically downstream of Sonic hedgehog (Shh) in the limb bud. We analyze PTC expression during chicken neural and somite development and find it expressed in all regions of these tissues known to be responsive to Sonic hedgehog signal. As in the limb bud, ectopic expression of Sonic hedgehog leads to ectopic induction of PTC in the neural tube and paraxial mesoderm. This conservation of regulation allows us to use PTC as a marker for Sonic hedgehog response. The pattern of PTC expression suggests that Sonic hedgehog may play an inductive role in more dorsal regions of the neural tube than have been previously demonstrated. Examination of the pattern of PTC expression also suggests that PTC may act in a negative feedback loop to attenuate hedgehog signaling.

‣ Axial (HNF3beta) and retinoic acid receptors are regulators of the zebrafish sonic hedgehog promoter.

Chang, B E; Blader, P; Fischer, N; Ingham, P W; Strähle, U
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/07/1997 Português
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The signalling molecule Sonic hedgehog is involved in a multitude of distinct patterning processes during vertebrate embryogenesis. In the nascent body axis of the zebrafish embryo, sonic hedgehog is co-expressed with axial (HNF3beta in mammals), a transcription regulator of the winged helix family. We show here that misexpression of axial leads to ectopic activation of sonic hedgehog expression in the zebrafish, suggesting that axial is a regulator of sonic hedgehog transcription. The sonic hedgehog gene was cloned from zebrafish and its promoter was characterized with respect to activation by axial. Expression of axial or rat HNF3beta in HeLa cells results in activation of co-transfected sonic hedgehog promoter-CAT fusion genes. This effect is mediated by two Axial (HNF3beta) recognition sequences. We furthermore identified a retinoic acid response element (RARE) in the sonic hedgehog upstream region which can be bound by retinoic acid receptor (RAR) and retinoid X receptor (RXR) heterodimers in vitro and confers retinoic acid inducibility to the sonic hedgehog promoter in the HeLa cell system. Our results suggest that both Axial (HNF3beta) and retinoic acid receptors are direct regulators of the sonic hedgehog gene.

‣ Localization of Sonic Hedgehog secreting and receiving cells in the developing and adult rat adrenal cortex

Guasti, Leonardo; Paul, Alex; Laufer, Ed; King, Peter
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Sonic hedgehog signaling was recently demonstrated to play an important role in murine adrenal cortex development. The organization of the rat adrenal differs from that of the mouse, with the zona glomerulosa and zona fasciculata separated by an undifferentiated zone in the rat, but not in the mouse. In the present study we aimed to determine the mRNA expression patterns of Sonic hedgehog and the hedgehog signaling pathway components Patched-1 and Gli1 in the developing and adult rat adrenal. Sonic hedgehog expression was detected at the periphery of the cortex in cells lacking CYP11B1 and CYP11B2 expression, while signal-receiving cells were localized in the overlying capsule mesenchyme. Using combined in situ hybridization and immunohistochemistry we found that the cells expressing Sonic hedgehog lie between the CYP11B2 and CYP11B1 layers, and thus Sonic hedgehog expression defines one cell population of the undifferentiated zone.

‣ Increased Production of Sonic Hedgehog by Ballooned Hepatocytes

Rangwala, Fatima; Guy, Cynthia D.; Lu, Jiuyi; Suzuki, Ayako; Burchette, James L.; Abdelmalek, Manal F.; Chen, Wei; Diehl, Anna Mae
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Ballooned hepatocytes distinguish nonalcoholic steatohepatitis (NASH) from steatosis. Such cells contain dilated endoplasmic reticulum and ubiquitin aggregates, characteristics of endoplasmic reticulum stress. Hepatocyte ballooning increases risk for fibrosis in NASH, suggesting ballooned hepatocytes release pro-fibrogenic factors. Hedgehog ligands function as pro-fibrogenic factors in liver diseases, but mechanisms for Hedgehog ligand production remain poorly understood. We evaluated the hypothesis that endoplasmic reticulum stress induces hepatocyte production of hedgehog ligands that provide paracrine pro-fibrogenic signals to neighboring cells. In livers from NASH patients, keratin 8/18 and ubiquitin staining demonstrated enlarged, keratin 8/18-negative/ubiquitin-positive hepatocytes (ballooned hepatocytes) that were positive for Sonic hedgehog. In order to model endoplasmic reticulum stress in vitro, primary mouse hepatocytes were treated with tunicamycin. Compared to vehicle, tunicamycin significantly increased Sonic hedgehog and Indian hedgehog expression. Furthermore, conditioned medium from tunicamycin-treated hepatocytes increased Gli-luciferase reporter activity 14-fold more than conditioned medium from vehicle-treated hepatocytes. Cyclopamine (hedgehog signaling inhibitor) abrogated the effect of conditioned medium from tunicamycin-treated hepatocytes...

‣ Sonic Hedgehog Activation Is Implicated in Diosgenin-Induced Megakaryocytic Differentiation of Human Erythroleukemia Cells

Ghezali, Lamia; Liagre, Bertrand; Limami, Youness; Beneytout, Jean-Louis; Leger, David Yannick
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 16/04/2014 Português
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Differentiation therapy is a means to treat cancer and is induced by different agents with low toxicity and more specificity than traditional ones. Diosgenin, a plant steroid, is able to induce megakaryocytic differentiation or apoptosis in human HEL erythroleukemia cells in a dose-dependent manner. However, the exact mechanism by which diosgenin induces megakaryocytic differentiation has not been elucidated. In this study, we studied the involvement of Sonic Hedgehog in megakaryocytic differentiation induced by diosgenin in HEL cells. First, we showed that different elements of the Hedgehog pathway are expressed in our model by qRT-PCR. Then, we focused our interest on key elements in the Sonic Hedgehog pathway: Smoothened receptor, GLI transcription factor and the ligand Sonic Hedgehog. We showed that Smoothened and Sonic Hedgehog were overexpressed in disogenin-treated cells and that GLI transcription factors were activated. Then, we showed that SMO inhibition using siSMO or the GLI antagonist GANT-61, blocked megakaryocytic differentiation induced by diosgenin in HEL cells. Furthermore, we demonstrated that Sonic Hedgehog pathway inhibition led to inhibition of ERK1/2 activation, a major physiological pathway involved in megakaryocytic differentiation. In conclusion...

‣ Cloning and bioinformatical analysis of the N-terminus of the sonic hedgehog gene☆

Zhang, Yi; Zhao, Shu; Dong, Weiren; He, Suifen; Wang, Haihong; Zhang, Lihua; Tang, Yinjuan; Guo, Jiasong; Guo, Suiqun
Fonte: Medknow Publications & Media Pvt Ltd Publicador: Medknow Publications & Media Pvt Ltd
Tipo: Artigo de Revista Científica
Publicado em 25/01/2013 Português
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The sonic hedgehog protein not only plays a key role in early embryonic development, but also has essential effects on the adult nervous system, including neural stem cell proliferation, differentiation, migration and neuronal axon guidance. The N-terminal fragment of sonic hedgehog is the key functional element in this process. Therefore, this study aimed to clone and analyze the N-terminal fragment of the sonic hedgehog gene. Total RNA was extracted from the notochord of a Sprague-Dawley rat at embryonic day 9 and the N-terminal fragment of sonic hedgehog was amplified by nested reverse transcription-PCR. The N-terminal fragment of the sonic hedgehog gene was successfully cloned. The secondary and tertiary structures of the N-terminal fragment of the sonic hedgehog protein were predicted using Jpred and Phyre online.

‣ Sonic hedgehog elevates N-myc gene expression in neural stem cells★

Liu, Dongsheng; Wang, Shouyu; Cui, Yan; Shen, Lun; Du, Yanping; Li, Guilin; Zhang, Bo; Wang, Renzhi
Fonte: Medknow Publications & Media Pvt Ltd Publicador: Medknow Publications & Media Pvt Ltd
Tipo: Artigo de Revista Científica
Publicado em 05/08/2012 Português
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Proliferation of neural stem cells is regulated by the secreted signaling molecule sonic hedgehog. In this study, neural stem cells were infected with recombinant adeno-associated virus expressing sonic hedgehog-N-enhanced green fluorescent protein. The results showed that overexpression of sonic hedgehog in neural stem cells induced the increased expression of Gli1 and N-myc, a target gene of sonic hedgehog. These findings suggest that N-myc is a direct downstream target of the sonic hedgehog signal pathway in neural stem cells. Sonic hedgehog and N-myc are important mediators of sonic hedgehog-induced proliferation of neural stem cells.

‣ Central role for Sonic hedgehog-triggered pericytes in hindbrain choroid plexus development

Yang, Peter
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
Português
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The choroid plexus is an organ within each brain ventricle comprised of elaborate folds of epithelium (CPe) and vasculature. It performs numerous functions essential for brain development and health, including secretion of cerebrospinal fluid (CSF) and acting as the blood-CSF barrier. Functionality requires: (1) that CPe and vasculature develop in register and in close proximity, so that the CPe ensheaths the vasculature at a high surface area to volume ratio, which permits efficient CSF secretion; and (2) that CPe barrier integrity is sustained throughout choroid plexus expansion. Genetic experiments in mouse embryos have identified a central role for Sonic hedgehog (Shh) in coordinating these developmental challenges. Specifically, Shh is secreted by differentiated CPe and drives choroid plexus expansion. In the absence of Shh, a hypoplastic choroid plexus forms, which is deficient in CPe, vasculature, and villous folds. Two choroid plexus cell populations respond to Shh: (1) rhombic lip-resident CPe progenitor cells and (2) vascular pericytes. Here, I present evidence that canonical Shh signaling to CPe progenitors alone is insufficient to fully drive their proliferation at normal rates. Rather, Shh-triggered pericytes appear to secondarily boost CPe progenitor cell proliferation...

‣ The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma

He, Xuelian; Zhang, Liguo; Chen, Ying; Remke, Marc; Shih, David; Lu, Fanghui; Wang, Haibo; Deng, Yaqi; Yu, Yang; Xia, Yong; Wu, Xiaochong; Ramaswamy, Vijay; Hu, Tom; Wang, Fan; Zhou, Wenhao; Burns, Dennis K.; Kim, Se Hoon; Kool, Marcel; Pfister, Stefan M.
Fonte: Harvard University Publicador: Harvard University
Tipo: Artigo de Revista Científica
Português
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Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G-protein Gsα, as a potent tumor suppressor gene that defines a subset of aggressive Sonic Hedgehog (Shh)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically-distinct progenitors is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gsα is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh-signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas mutants. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gsα that acts as a molecular link across Shh-group medulloblastomas of disparate cellular and anatomical origins, illuminating G-protein modulation as a potential therapeutic avenue.

‣ Sonic hedgehog signaling regulates mode of cell division of early cerebral cortex progenitors and increases

Araújo, Geissy L. L.; Araújo, Jessica A. M.; Shroeder, Tim; Tort, Adriano; Costa, Marcos
Fonte: Universidade Federal do Rio Grande do Norte Publicador: Universidade Federal do Rio Grande do Norte
Tipo: Artigo de Revista Científica
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The morphogen Sonic Hedgehog (SHH) plays a critical role in the development of different tissues. In the central nervous system, SHH is well known to contribute to the patterning of the spinal cord and separation of the brain hemispheres. In addition, it has recently been shown that SHH signaling also contributes to the patterning of the telencephalon and establishment of adult neurogenic niches. In this work, we investigated whether SHH signaling influences the behavior of neural progenitors isolated from the dorsal telencephalon, which generate excitatory neurons and macroglial cells in vitro. We observed that SHH increases proliferation of cortical progenitors and generation of astrocytes, whereas blocking SHH signaling with cyclopamine has opposite effects. In both cases, generation of neurons did not seem to be affected. However, cell survival was broadly affected by blockade of SHH signaling. SHH effects were related to three different cell phenomena: mode of cell division, cell cycle length and cell growth. Together, our data in vitro demonstrate that SHH signaling controls cell behaviors that are important for proliferation of cerebral cortex progenitors, as well as differentiation and survival of neurons and astroglial cells.

‣ The HMG Box Transcription Factor Gene Sox14 Marks a Novel Subset of Ventral Interneurons and Is Regulated by Sonic Hedgehog

Hargrave, Murray; Karunaratne, Asanka; Cox, Liza; Wood, Stephen Andrew; Koopman, Peter; Yamada, Toshiya
Fonte: Academic Press Publicador: Academic Press
Tipo: Artigo de Revista Científica
Publicado em //2000 Português
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Cell-type diversity along the dorsoventral axis of the developing neural tube is influenced by factors secreted by groups of cells at the dorsal and ventral midline. Upon reception of these signals, precursor cells express specific sets of transcription factors which, in turn, play critical roles in cell-type specification. Here we report the cloning and characterization of Sox14, a novel and highly conserved member of the Sry-related Sox transcription factor gene family, in mouse and chick. Sox14 expression is restricted to a limited population of neurons in the developing brain and spinal cord of both species. Sox14 marks a subset of interneurons at a defined dorsoventral position adjacent to ventral motor neurons in the spinal cord. In vivo grafting of chick notochord tissue to ectopic positions adjacent to the developing spinal cord altered the expression domain of Sox14. Furthermore, expression of Sox14 in spinal cord explants was found to be regulated by Sonic hedgehog in a dose-dependent manner. These data implicate a novel class of transcription factors in dorsoventral cell-type specification in the spinal cord.; http://www.sciencedirect.com/science/journal/00121606

‣ Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog

Solomon, B.; Thompson, E.
Fonte: British Med Journal Publ Group Publicador: British Med Journal Publ Group
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
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BACKGROUND: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog(SHH) was the first such gene discovered; mutations in SHH remain the most common cause of nonchromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. OBJECTIVE: To characterise genetic and clinical findings in individuals with SHH mutations. METHODS: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. RESULTS: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%...

‣ Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-induronic acid function as Sonic Hedgehog co-receptors to promote proliferation

Witt, R.; Hecht, M.L.; Pazyra-Murphy, M.; Cohen, S.; Noti, C.; van Kuppevelt, T.; Fuller, M.; Chan, J.; Hopwood, J.; Seeberger, P.; Segal, R.
Fonte: Amer Soc Biochemistry Molecular Biology Inc Publicador: Amer Soc Biochemistry Molecular Biology Inc
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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Sonic Hedgehog (Shh) signaling is crucial for growth, cell fate determination, and axonal guidance in the developing nervous system. Although the receptors Patched (Ptch1) and Smoothened (Smo) are required for Shh signaling, a number of distinct co-receptors contribute to these critical responses to Shh. Several membrane-embedded proteins such as Boc, Cdo, and Gas1 bind Shh and promote signaling. In addition, heparan sulfate proteoglycans (HSPGs) have also been implicated in the initiation of Shh responses. However, the attributes of HSPGs that function as co-receptors for Shh have not yet been defined. Here, we identify HSPGs containing a glypican 5 core protein and 2-O-sulfo-iduronic acid residues at the nonreducing ends of the glycans as co-receptors for Shh. These HSPG co-receptors are expressed by cerebellar granule cell precursors and promote Shh binding and signaling. At the subcellular level, these HSPG co-receptors are located adjacent to the primary cilia that act as Shh signaling organelles. Thus, Shh binds to HSPG co-receptors containing a glypican 5 core and 2-O-sulfo-iduronic acid to promote neural precursor proliferation.; Rochelle M. Witt, Marie-Lyn Hecht, Maria F. Pazyra-Murphy, Samuel M. Cohen Christian Noti, Toin H. van Kuppevelt...

‣ Zur Rolle des Sonic Hedgehog Aktivierungsweges in der Entwicklung des humanen fetalen Gehirns; About the role of Sonic Hedgehog in the development of the normal human brain

Tichy, Julia Frederike
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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Der Sonic Hedgehog-Signalweg spielt eine zentrale Rolle in der embryonalen Entwicklung des zentralen Nervensystems. Beispielsweise reguliert Shh die Zellproliferation, die Migration sowie die Steuerung der Apoptose. Bislang existieren jedoch kaum Daten über die Verteilung von Sonic Hedgehog (Shh) und seinen Rezeptor- und Signalmolekülen im sich entwickelnden normalen humanen ZNS. Hieraus resultiert das Ziel der vorliegenden Arbeit, Shh selbst, sowie Patched, Smoothened, Gli1, Gli2 und Gli3 in ihrer räumlich-zeitlichen Verteilung im humanen ZNS darzustellen. Hierzu wurden 22 fetale Groß- und Kleinhirne zwischen der 12. und 28. Schwangerschaftswoche mittels Immunhistochemie untersucht. Alle sechs untersuchten Moleküle lassen sich in allen cerebellären, als auch neokortikalen Rindenschichten des sich entwickelnden fetalen Gehirns darstellen. In den fetalen Rindenschichten des Großhirnes lässt sich eine starke Immunreaktivitätsrate für alle untersuchten Signalmoleküle in den ventrikelnahen, proliferationsreichen Rindenschichten zeigen. Im zeitlichen Verlauf konnte ein Abfall (für Shh signifikant) der Immunreaktivitätsintensität des Signalweges in den proliferationsreichen Zonen und zugleich ein Anstieg in den ventrikelfernen Schichten beobachtet werden. Bei der Betrachtung der humanen Kleinhirnentwicklung zeichnet sich die Äußere Körnerzellschicht...

‣ Étude de la signalisation Sonic Hedgehog dans le guidage des axones de la rétine lors de l’établissement de la vision binoculaire

Fabre, Pierre J.
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
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Chez les animaux à vision binoculaire, la vision tridimensionnelle permet la perception de la profondeur grâce à l'intégration de l'information visuelle en provenance des deux yeux. La première étape de cette intégration est rendue possible anatomiquement par la ségrégation des axones controlatéraux et ipsilatéraux des cellules ganglionnaires de la rétine (CGR) au niveau du chiasma optique. Les axones controlatéraux croisent la ligne médiane au chiasma en route du nerf optique vers le cerveau. À l’inverse, les axones ipsilatéraux s'écartent du chiasma et continuent dans le tractus optique ipsilatéral, en évitant la ligne médiane vers leurs cibles cérébrales. Les mécanismes moléculaires à la base de ce phénomène ne sont pas complètement compris. Les études présentées dans cette thèse montrent que Boc, le récepteur de Sonic Hedgehog (Shh) dans le guidage axonal, est enrichi dans les CGRs ipsilatérales de la rétine en développement. La présence de Shh sur la ligne médiane, et le mode d'expression complémentaire du récepteur nous ont conduit à émettre l'hypothèse que Shh pourrait repousser les axones ipsilatéraux au niveau du chiasma en activant le récepteur Boc. Conformément à cette hypothèse...

‣ PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation

Sabbatino, Francesco; Wang, Yangyang; Wang, Xinhui; Flaherty, Keith T.; Yu, Ling; Pepin, David; Scognamiglio, Giosue'; Pepe, Stefano; Kirkwood, John M.; Cooper, Zachary A.; Frederick, Dennie T.; Wargo, Jennifer A.; Ferrone, Soldano; Ferrone, Cristina R.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
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Control of BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Growth factor receptor up-regulation is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that PDGFRα up-regulation causes BRAF-I resistance. PDGFRα inhibition by PDGFRα-specific short hairpin (sh)RNA and by PDGFRα inhibitors restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. This effect reflects the inhibition of ERK and AKT activation which is associated with BRAF-I resistance of melanoma cells. PDGFRα up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment. Similarly to PDGFRα inhibition, Shh inhibition by LDE225 restores and increases melanoma cells' sensitivity to BRAF-I. These effects are mediated by PDGFRα down-regulation and by ERK and AKT inhibition. The clinical relevance of these data is indicated by the association of PDGFRα up-regulation in melanoma matched biopsies of BRAF-I +/- MEK inhibitor treated patients with shorter time to disease progression and less tumor regression. These findings suggest that monitoring patients for early PDGFRα up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRα or Shh inhibitors.

‣ Neogenina 1 actúa como un blanco transcripcional directo de la vía Sonic Hedgehog/Gli en línea celular de neuroblastoma humano

Espinoza Giacomozzi, Natalie Andrea
Fonte: Universidad de Chile Publicador: Universidad de Chile
Tipo: Tesis
Português
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Memoria para optar al título Profesional de Bioquímico; El desarrollo embrionario en vertebrados es coordinado por una red de señales y factores de crecimiento que comandan diferentes procesos celulares. Sonic Hedgehog (SHH), es un ligando considerado como un regulador maestro que dirige los procesos de proliferación celular, migración, apoptosis, sobrevida y diferenciación celular. SHH es liberado al medio y una vez que llega a su célula blanco, ésta activa una compleja vía de señalización intracelular, que finalmente, moviliza a los factores transcripcionales Gli. Estos últimos activan la expresión de genes blanco de la vía reconociendo secuencias específicas en el ADN llamadas GBS (del inglés “Gli Binding Site”). Además, se sabe que una desregulación en la vía de SHH/Gli puede llevar al desarrollo de cáncer, como ocurre en los casos del meduloblastoma y el cáncer de células basales de la piel, entre otros. Recientemente, por resultados obtenidos en el laboratorio, se estableció que en los modelos de ratón y pez cebra, el gen neogenina 1 es un blanco transcripcional de la vía SHH/Gli. Considerando la conservación evolutiva de la vía de SHH/Gli y la característica multifuncional de la proteína Neogenina 1...

‣ The Role of Sonic Hedgehog in Outflow Tract Development

Dyer, Laura Ann
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação Formato: 49036095 bytes; application/pdf
Publicado em //2009 Português
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The two major contributing populations to the outflow tract of the heart are the secondary heart field and the cardiac neural crest. These two populations are responsible for providing the myocardium that supports the outflow tract valves, the smooth muscle that surrounds these valves and the outflow vessels themselves, and the septum that divides the primitive, single outflow tract into an aorta and pulmonary trunk. Because the morphogenesis of this region is so complex, its development is regulated by many different signaling pathways. One of these pathways is the Sonic hedgehog pathway. This thesis tests the hypothesis that Sonic hedgehog induces secondary heart field proliferation, which is necessary for normal outflow tract development. To address this hypothesis, I took advantage of small chemical antagonists and agonists to determine how too little or too much hedgehog signaling would affect the secondary heart field, both in in vitro explants and in vivo. I have determined that Sonic hedgehog signaling maintains proliferation in a subset of secondary heart field cells. This proliferation is essential for generating enough myocardium and smooth muscle and also for the cardiac neural crest to septate the outflow tract into two equal-sized vessels. Up-regulating hedgehog signaling induces proliferation...

‣ An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development

Lee, Jeffrey D; Krause, Petra; Gaiano, Nicholas; Vaz da Silva de Castro Nery, Susana; Kohtz, Jhumku; Fishell, Gord; Loomis, Cynthia A; Treisman, Jessica E
Fonte: Academic Press Publicador: Academic Press
Tipo: Artigo de Revista Científica
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The Drosophila Hedgehog protein and its vertebrate counterpart Sonic hedgehog are required for a wide variety of patterning events throughout development. Hedgehog proteins are secreted from cells and undergo autocatalytic cleavage and cholesterol modification to produce a mature signaling domain. This domain of Sonic hedgehog has recently been shown to acquire an N-terminal acyl group in cell culture. We have investigated the in vivo role that such acylation might play in appendage patterning in mouse and Drosophila; in both species Hedgehog proteins define a posterior domain of the limb or wing. A mutant form of Sonic hedgehog that cannot undergo acylation retains significant ability to repattern the mouse limb. However, the corresponding mutation in Drosophila Hedgehog renders it inactive in vivo, although it is normally processed. Furthermore, overexpression of the mutant form has dominant negative effects on Hedgehog signaling. These data suggest that the importance of the N-terminal cysteine of mature Hedgehog in patterning appendages differs between species.