Aspectos moleculares da transformação celular induzida por Bcr-Abl.

Silva, Ana Elisa Barreiros Bueno da

doi:10.11606/T.42.2008.tde-03062008-153936

Home

Facilities

Doctoral Thesis

DOI

https://doi.org/10.11606/T.42.2008.tde-03062008-153936

Document

Doctoral Thesis

Author

Silva, Ana Elisa Barreiros Bueno da (Catálogo USP)

Full name

Ana Elisa Barreiros Bueno da Silva

Institute/School/College

Instituto de Ciências Biomédicas

Knowledge Area

Immunology

Date of Defense

2008-04-11

Published

São Paulo, 2008

Supervisor

Mendes, Joao Gustavo Pessini Amarante (Catálogo USP)

Committee

Mendes, Joao Gustavo Pessini Amarante (President)
Chammas, Roger
Hamerschlak, Nelson
Menck, Carlos Frederico Martins
Smaili, Soraya Soubhi

Title in Portuguese

Aspectos moleculares da transformação celular induzida por Bcr-Abl.

Keywords in Portuguese

Apoptose
Bcr-Abl
Leucemia mielóide crônica
Proteoma
Tirosina-quinase
Transformação celular

Abstract in Portuguese

As leucemias cromossomo Ph-positivas estão intimamente associadas à expressão da tirosina-quinase Bcr-Abl. Esta oncoproteína promove independência de fatores de crescimento, alterações na adesão e inibição da apoptose por mecanismos ainda não totalmente elucidados. O objetivo desse estudo foi avaliar a contribuição da atividade quinase de Bcr-Abl para seu potencial anti-apoptótico e identificar alterações moleculares envolvidas na transformação celular induzida por essa proteína. Nossos resultados sugerem que a resistência à apoptose não depende da manutenção constante da atividade tirosina-quinase de Bcr-Abl, tampouco da presença de proteínas fosforiladas em tirosina. A comparação do proteoma de células HL-60.vetor e HL-60.Bcr-Abl revelou que a presença de Bcr-Abl causa alterações profundas no padrão de expressão protéica. As proteínas afetadas estão associadas a diversos processos celulares, como adesão, transdução de sinais, proliferação e morte celular. Esses achados devem contribuir para a identificação de novos marcadores de prognóstico e alvos terapêuticos.

Title in English

Molecular aspects of Bcr-Abl-induced cell transformation.

Keywords in English

Apoptosis
Bcr-Abl
Cell transformation
Chronic myeloid leukemia
Proteome
Tyrosine kinase

Abstract in English

Ph chromosome-positive leukemias are closely associated with the expression of Bcr-Abl tyrosine kinase. This oncoprotein promotes growth factor independence, alters cell adhesion and confers resistance to apoptosis by mechanisms that are not fully understood. The aim of this study was to evaluate the contribution of Bcr-Abl kinase activity for its antiapoptotic potential and identify molecular alterations involved in Bcr-Abl-induced cell malignant transformation. Our results suggest that Bcr-Abl is not required to be constantly active to maintain the resistance to apoptosis and pY-containing proteins may not be responsible for the antiapoptotic effect of Bcr-Abl. The comparison between the proteome of HL-60.vector and HL-60.Bcr-Abl cells revealed that the presence of Bcr-Abl alters the expression of a great variety of proteins. The affected molecules are associated with several cellular processes, including cell adhesion, signal transduction, proliferation and cell death. Our findings might help the identification of new prognostic markers and therapeutic targets.

WARNING - Viewing this document is conditioned on your acceptance of the following terms of use:
This document is only for private use for research and teaching activities. Reproduction for commercial use is forbidden. This rights cover the whole data about this document as well as its contents. Any uses or copies of this document in whole or in part must include the author's name.

AnaElisaBarreirosBuenodaSilva_Doutorado.pdf (6.09 Mbytes)

Publishing Date

2008-06-11

Derived works

WARNING: The material described below relates to works resulting from this thesis or dissertation. The contents of these works are the author's responsibility.

BRUMATTI, G, et al. Conversion of CD95 (Fas) Type II into Type I signaling by sub-lethal doses of cycloheximide [doi:10.1016/j.yexcr.2007.11.003]. Experimental Cell Research [online], 2008, vol. 314, p. 554-563.
BUENO-DA-SILVA, A.E.B., et al. Bcr-Abl-mediated resistance to apoptosis is independent of constant tyrosine-kinase activity [doi:10.1038/sj.cdd.4401210]. Cell Death and Differentiation [online], 2003, vol. 10, p. 592-598.
CASTRO, Fabíola Attié de, et al. Apoptosis resistance in chronic myelogenous leukemia. Einstein (São Paulo), 2005, vol. 3, p. 207-212.
CASTRO, Fabíola Attié de, et al. Genomic Approach to Understand the Mechanisms Involved in BCR-ABL Mediated Resistance to Apoptosis. Applied Cancer Research, 2005, vol. v. 2, nº Supplement, p. 54-55. Abstract.
De Carvalho, D D, et al. BCR ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients [doi:10.1038/onc.2010.409]. Oncogene (Basingstoke) [online], 2010, vol. 30, p. 223-233.
JACYSYN, J. F., et al. Thymic Epithelial Cells Mediate a Bcl-2-Independent Protection of Single-Positive Thymocytes from Dexamethasone-Induced Apoptosis [doi:10.1006/excr.2001.5406]. Experimental Cell Research [online], 2002, vol. 272, p. 119-126.
RAMOS, M.G., et al. Butyrate Increases Apoptosis Induced by Different Antineoplastic Drugs in Monocytic Leukemia Cells [doi:10.1159/000081942]. Chemotherapy (Basel) [online], 2004, vol. 50, p. 221-228.
SILVA, S.O., et al. Neutrophils as a specific target for melatonin and kynuramines: effects on cytokine release [doi:10.1016/j.jneuroim.2004.07.015]. Journal of Neuroimmunology [online], 2004, vol. 156, p. 146-152.
TANJONI, I., et al. Jararhagin, a snake venom metalloproteinase, induces a specialized form of apoptosis (anoikis) selective to endothelial cells [doi:10.1007/s10495-005-2945-1]. Apoptosis (London) [online], 2005, vol. 10, p. 851-861.
BALDO, C, et al. BnP1, a novel P-I metalloproteinase from Bothrops neuwiedi venom: Biological effects benchmarking relatively to jararhagin, a P-III SVMP? [doi:10.1016/j.toxicon.2007.08.005]. Toxicon [online], 2008, vol. 51, p. 54-65.
AMARANTE-MENDES, G.P., et al. Protection Of Thymocytes From Glucocorticoid-Induced Apoptosis By A Thymic Stromal Cell Clone (2bh4). In IX Reunião Anual da Federação de Sociedades de Biologia Experimental. Caxambu, Minas Gerais, 1994. Resumo.
BUENO-DA-SILVA, A.E.B., et al. Efeito da inibição da atividade tirosina-quinase na resistência a apoptose mediada por Bcr-Abl. In 8 Simpósio Internacional de Iniciação Científica da USP, São Paulo, 2000. Anais do Congresso., 2000. Resumo.
BUENO-DA-SILVA, A.E.B., et al. Efeito da inibição da atividade tirosina-quinase na resistência a apoptose mediada por Bcr-Abl. In III Congresso do Instituto de Ciências Biomédicas da Universidade de São Paulo, São Paulo, 2001. Anais do Congresso., 2001. Resumo.
BUENO-DA-SILVA, A.E.B., et al. Efeito da inibição da atividade tirosina-quinase na resistência a apoptose mediada por Bcr-Abl. In VIII Jornada Nacional de Iniciação Científica, realizada durante a 53a Reunião Anual SBPC, Salvador, 2001. Anais do Congresso., 2001. Resumo.
BUENO-DA-SILVA, A.E.B., et al. Inhibition of Bcr-Abl tyrosine-kinase activity does not impair its anti-apoptotic effect. In XXIV Congresso Brasileiro de Imunologia, Águas de Lindóia, 1999. Anais do Congresso., 1999. Resumo.
CERONE, I. H., et al. Modulation of BCG-induced inflammatory reactions by concomitant administration of apoptotic cells. In XXIV Congresso da Sociedade Brasileira de Imunologia, Águas de LIndóia, 1999. Anais do Congresso., 1999. Abstract.
ONOFRE, P. C. G., et al. Produção e purificação de Anexina V recombinante, padronizada em ensaios de apoptose. In 10o Simpósio Internacional de Iniciação Científica da USP, Ribeirão Preto, 2002. Anais do Congresso., 2002. Resumo.
CARVALHO, D. D., et al. Human Tumor-Associated Antigen PRAME Overexpression is Associated with Chronic Myeloid Leukemia Progression. In XXXI Meeting of the brazilian society for Immunology: Signaling in the immune system., Búzios - RJ, 2006. XXXI Meeting of the brazilian society for Immunology: Signaling in the immune system., 2006. Abstract. Available from: http://www.sbi.org.br/sbi2006/resumos/sbi2006_rs_tu.pdf.
CARVALHO, D. D., et al. PRAME Expression is Associated with Down-Regulation of TRAIL in Chronic Myeloid Leukemia. In VIII São Paulo Research Conference - Cancer 2007: From Molecular Biology to Treatment, São Paulo, 2007. Applied Cancer Research., 2007. Abstract. Available from: http://appliedcr.org/ojsystem/index.php/appliedcr/article/view/91/88.
CASTRO, Fabíola Attié de, et al. Genomic Approach to Understand the Mechanisms Involved in BCR-ABL-Mediated Resistance to Apoptosis. In 4th São Paulo Research Conference - Cancer Today, from molecular biology to treatment, 2005. Anais do Evento., 2005. Abstract.
LEROY, J. M. G., et al. Bcr/Abl induces faim overexpression, a potencial new target for therapy. In XXXI Meeting of the Brazilian Society for immunology, Buzios, 2006. XXXI Meeting of the Brazilian society for immunology., 2006. Resumo.
LEROY, J. M. G., et al. Genomic approach to understand the mecanisms involved in Bcr-Abl mediated resistance to apoptosis. In The 6th International Cell Death Symposium, Angra dos Reis, 2006. he 6th International Cell Death Symposium on the mecanisms of cell death in cancer and aging., 2006. Abstract.
PEREIRA, W. O., et al. ALX downregulation in Chronic Myeloid Leukemia is Bcr-Abl tyrosine-kinase activity dependent. In 13th International Congress of Immunology, Rio de Janeiro, 2007. 13th International Congress of Immunology., 2007. Abstract.
PEREIRA, W. O., et al. Down regulation of hematopoietic SH2 domain containing (HSH2D) in the progression of the Chronic Myelogenous Leukemia. In XXXI Meeting of the Brazilian Society for Immunology, Búzios, 2006. XXXI Meeting of the Brazilian Society for Immunology., 2006. Abstract.
TANJONI, I., et al. Jararhagin selectively induced anoikis in endothelial cells. In International Symposium on Extracellular Matrix, Angra dos Reis, 2004. Anais do Evento., 2004. Abstract.
YON, M., et al. Conversion of fas Type II into Fas type I cells by sublethal doses of cycloheximide. In XXVIII Meeting of the Brazilian Society of Immunology, Rio de Janeiro, 2003. Anais do Congresso., 2003. Resumo.
YON, M., et al. Correlation between metabolic alterations and apoptosis resistance confered by Bcr-Abl expression. In The 6th International Cell Death Symposium on Mechanisms of Cell Death and Aging, Angra dos Reis, 2006. The 6th International Cell Death Symposium on Mechanisms of Cell Death and Aging., 2006. Abstract.