Registro:
Documento: | Tesis Doctoral |
Disciplina: | biologia |
Título: | El receptor acoplado a proteína G del herpes virus asociado al sarcoma de Kaposi (Kaposi's Sarcoma associated herpevirus o KSHV) es una oncoproteína viral y un activador angiogénico |
Título alternativo: | The G protein coupled receptor encoded by the Kaposi's Sarcoma associated virus is a viral oncoprotein and an angiogenic activator |
Autor: | Bais, Carlos E. |
Editor: | Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales |
Filiación: | Weill Cornell Medical College
|
Publicación en la Web: | 2017-03-01 |
Fecha de defensa: | 2000 |
Fecha en portada: | 2000 |
Grado Obtenido: | Doctorado |
Título Obtenido: | Doctor en Ciencias Biológicas |
Director: | Mesri, Enrique A. |
Director Asistente: | Levin, Mariano |
Idioma: | Español |
Tema: | biología/biología molecular y celular biología/biomedicina
|
Formato: | PDF |
Handle: |
http://hdl.handle.net/20.500.12110/tesis_n3288_Bais |
PDF: | https://bibliotecadigital.exactas.uba.ar/download/tesis/tesis_n3288_Bais.pdf |
Registro: | https://bibliotecadigital.exactas.uba.ar/collection/tesis/document/tesis_n3288_Bais |
Ubicación: | Dep.BIO 003288 |
Derechos de Acceso: | Esta obra puede ser leída, grabada y utilizada con fines de estudio, investigación y docencia. Es necesario el reconocimiento de autoría mediante la cita correspondiente. Bais, Carlos E.. (2000). El receptor acoplado a proteína G del herpes virus asociado al sarcoma de Kaposi (Kaposi's Sarcoma associated herpevirus o KSHV) es una oncoproteína viral y un activador angiogénico. (Tesis Doctoral. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales.). Recuperado de http://hdl.handle.net/20.500.12110/tesis_n3288_Bais |
Abstract:
The Kaposi's Sarcoma-associated herpesvirus (KSHV-HHV-8)is a γ-2 herpesvirus that isimplicated in the pathogenesis of Kaposi's sarcoma and of primary effusion B-celllymphomas (PELs), it encode putative oncogenes, and genes that may cause Kaposi'ssarcoma lesions by stimulating angiogenesis. The G-protein-coupled receptor encoded byan open reading frame (ORF 74) of KSHV is expressed in Kaposi's Sarcoma lesions andin PELs, and stimulates signaling pathways linked to cell proliferation in a constitutive (agonist-independent) way. Here we show that signaling by this G-Protein Coupled Receptor leads to cell transformation an tumorigenicity, and induces a switch to anangiogenic phenotype mediated by vascular endothelial growth factor (VEGF), anangiogenesis and Kaposi's-spindle cell growth factor. We find that this receptor canactivate ( in HEK293T) two protein kinases, JNK/SAPK and p38MAPK, by triggeringsignaling cascades like the ones induced by inflammatory cytokines that are angiogenicactivators and mitogens for Kaposi's sarcoma-cells and B cells. Although this is asuggestive result, when we express KSHV-GPCR in different cell types it activatedifferent signaling cascades, and induces different phenotypes. Using pathway specificdominant negatives and pharmacological inhibitors we show that, in the cell line NIH3T3,the activation of JNK and p38 play a major rol in the molecular mechanism of KSHV-GPCRinduced cell transformation. Endothelial cells play a central rol in kaposi's sarcoma pathogenesis. KSHV infectsendothelial cells and spindle-like cells, of suspected endothelial origin, wich are present inthe kaposi's sarcoma lesions. Therefore, in the context of viral infection, KSHV-GPCR isexpressed in endothelial cells. As the expression of KSHV-GPCR has different biologicaland biochemical effects in different cell types we decide to study the consecuences of KSHV-GPCR expression in human primary endothelial cells. KSHV-GPCR expression in endothelial cells induce strong morphologic changes,modifications in the citoskeleton structure, secretion of metaloproteases and resistence toserum starvation mediated by activation of the PI3K/AKT pathway's. All those changesare reminiscent of the transformed phenotype. Usually, the expression of transforming oncogenes in primary cells induces shortage oftelomeres, premature senescence, and cell death. In sharp contrast the expression of KSHV-GPCR in primary endothelial human cells stabilize telomere length, by analternative mechanism independent of telomerase activity (Alternative Lengthening of Telomeres or ALT ), and inmortalize endothelial cells. To our knowledge this is the firstdemostration that a protein encoded by KSHV is able to inmortailize primary human cells. Thus using a KSHV oncogenic protein we created a new inmortilized endothelial cell linethat we call Ecs-KSGPCR. As predicted by the multistep carcinogenesis hypotesis, ourpreliminary experiments suggest that the mechanisms of Terminal Proliferation Arrest (TPA) are not completelly supressed by KSHV-GPCR and that additional oncogenicevents are necessary in order to fully transform human primary endothelial cells. Furtherresearch will determine wether other KSHV's oncogenes can cooperate oncogenicaly with KSHV-GPCR. KDR/VEGFR-2 and Tie-2 are endothelial specific tyrosine kinase receptors that play keyroles in vascular biology. These two receptors regulate cell survival and proliferation ofendothelial cells during angiogenesis, as a consequence of this they appear to beminimally expressed in quiescent endothelium in vivo, and they are down regulated after afew passages, in vitro, of primary endothelial cells. Surprisingly KDR and Tie-2 areoverexpressed in long term cultures of Ecs-KSGPCR. Altough in this work we show thatthe sustained expression of those receptors is functional, further experiments are requiredto determine if they play any rol in the inmortalization process. We conclude that KSHV-GPCR is a viral oncogene that can exploit cell signalingpathways to induce oncogenesis and angiogenesis in KSHV-mediated oncogenesis.
Citación:
---------- APA ----------
Bais, Carlos E.. (2000). El receptor acoplado a proteína G del herpes virus asociado al sarcoma de Kaposi (Kaposi's Sarcoma associated herpevirus o KSHV) es una oncoproteína viral y un activador angiogénico. (Tesis Doctoral. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales.). Recuperado de https://hdl.handle.net/20.500.12110/tesis_n3288_Bais
---------- CHICAGO ----------
Bais, Carlos E.. "El receptor acoplado a proteína G del herpes virus asociado al sarcoma de Kaposi (Kaposi's Sarcoma associated herpevirus o KSHV) es una oncoproteína viral y un activador angiogénico". Tesis Doctoral, Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales, 2000.https://hdl.handle.net/20.500.12110/tesis_n3288_Bais
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