Role of the C-terminal actin binding domain in BCR/ABL-mediated survival and drug resistance.
Br J Haematol
; 132(6): 774-83, 2006 Mar.
Article
em En
| MEDLINE
| ID: mdl-16487179
ABSTRACT
Philadelphia chromosome-positive, chronic myeloid leukaemia (CML) stem and progenitor cells have a survival and growth advantage compared with their normal counterparts. The mechanisms through which the BCR/ABL protein tyrosine kinase (PTK) induces these effects and the important domains within this protein are not fully defined. The F- and G-actin binding region of the BCR/ABL C-terminus may be important in BCR/ABL-mediated events, and we have investigated this by expressing a C-terminus deletion mutant of the temperature-sensitive BCR/ABL PTK, in a haemopoietic progenitor cell line, which models the chronic phase of CML. The truncated BCR/ABL PTK displayed similar levels of PTK activity when compared with wild type and activation of second messenger formation (in the form of sn-1,2-diacylglycerol) remains intact. On fibronectin substrata, localisation of the protein to the periphery of the cell was, however, dependent on the C-terminus of BCR/ABL PTK. Deletion of the C-terminus reversed both BCR/ABL-mediated apoptotic suppression and drug resistance although the progenitor cells did retain a proliferative advantage at low concentrations of growth factor. These results demonstrated that the C-terminal actin-binding domain of BCR/ABL is important for some of BCR/ABL PTK-mediated leukaemogenic effects.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
/
Leucemia Mielogênica Crônica BCR-ABL Positiva
/
Proteínas de Fusão bcr-abl
/
Actinas
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article