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Doctoral Thesis
DOI
10.11606/T.42.2009.tde-03022010-091640
Document
Author
Full name
Daniel Diniz de Carvalho
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2009
Supervisor
Committee
Mendes, Joao Gustavo Pessini Amarante (President)
Abdelhay, Eliana Saul Furquim Werneck
Barbuto, Jose Alexandre Marzagao
Camargo, Anamaria Aranha
Sogayar, Mari Cleide
Title in Portuguese
Regulação da expressão de SH3BGRL2, D53, PRAME, DAP12 e calcineurina A beta por BCR-ABL e consequências biológicas dessa regulação na LMC.
Keywords in Portuguese
PRAME
Apoptose
BCR-ABL
Células cultivadas de tumor
Expressão gênica (Regulação)
EZH2
Leucemia Mielóide Crônica
TRAIL
Abstract in Portuguese
Sabe-se que TRAIL é capaz de matar células tumorais de forma seletiva e que TRAIL tem sua expressão reduzida em diversos tumores, porém pouco se sabe sobre os mecanismos responsáveis pela sua inibição. Tendo em vista que a expressão de TRAIL pode ser regulada pelo Ácido Retinóico; que PRAME é capaz de inibir a via do ácido retinóico através da proteína EZH2 e que nós observamos anteriormente que a expressão de TRAIL esta diminuída em pacientes com LMC, nós decidimos investigar a associação entre PRAME, EZH2 e TRAIL na LMC. Nós demonstramos que PRAME, mas não EZH2, tem sua expressão aumentada em células BCR-ABL+ e sua expressão está associada com a progressão da LMC. Alem disto, existe uma correlação positiva entre PRAME e BCR-ABL e negativa entre PRAME e TRAIL nestes pacientes. A inibição da expressão de PRAME ou EZH2 por RNAi induziu um aumento da expressão de TRAIL. Estes dados revelam um novo mecanismo de regulação responsável por diminuir a expressão de TRAIL, e geram novos possíveis alvos para a terapia da LMC e, possivelmente, também para outros tumores.
Title in English
BCR-ABL-mediated regulation of SH3BGRL2, D53, PRAME, DAP12 e Calcineurin A beta and biological consequences of this regulation on CML.
Keywords in English
PRAME
Apoptosis
BCR-ABL
Chronic Myeloid Leukemia
Cultured tumor cells
EZH2
Gene expression (Regulation)
TRAIL
Abstract in English
TRAIL was shown to selectively kill tumor cells. Not surprisingly, TRAIL is down-regulated in a variety of tumor cells, but the mechanism responsible for TRAIL inhibition remains elusive. Because TRAIL can be regulate by retinoic acid; PRAME was shown to inhibit transcription of retinoic acid receptor target genes through the polycomb protein EZH2; and we have found that TRAIL is inversely correlated with BCR-ABL in CML patients, we decided to investigate the association of PRAME, EZH2 and TRAIL in BCR-ABL-positive leukemia. Here, we demonstrate that PRAME, but not EZH2, is up-regulated in BCR-ABL cells and is associated with the progression of disease in CML patients. In addition, PRAME expression is positively correlated with BCR-ABL and negatively with TRAIL in these patients. Importantly, knocking down of PRAME or EZH2 by RNA interference restores TRAIL expression. Our data reveal a novel regulatory mechanism responsible for lowering TRAIL expression and provide the basis of alternative targets for combined therapeutic strategies for CML.
 
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Publishing Date
2010-03-04
 
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