Global effects of BCR/ABL and TEL/PDGFRbeta expression on the proteome and phosphoproteome: identification of the Rho pathway as a target of BCR/ABL.

2.50
Hdl Handle:
http://hdl.handle.net/10541/75636
Title:
Global effects of BCR/ABL and TEL/PDGFRbeta expression on the proteome and phosphoproteome: identification of the Rho pathway as a target of BCR/ABL.
Authors:
Unwin, Richard D; Sternberg, David W; Lu, Yuning; Pierce, Andrew; Gilliland, D Gary; Whetton, Anthony D
Abstract:
Many leukemic oncogenes form as a consequence of gene fusions or mutation that result in the activation or overexpression of a tyrosine kinase. To identify commonalities and differences in the action of two such kinases, breakpoint cluster region (BCR)/ABL and TEL/PDGFRbeta, two-dimensional gel electrophoresis was employed to characterize their effects on the proteome. While both oncogenes affected expression of specific proteins, few common effects were observed. A number of proteins whose expression is altered by BCR/ABL, including gelsolin and stathmin, are related to cytoskeletal function whereas no such changes were seen in TEL/PDGFRbeta-transfected cells. Treatment of cells with the kinase inhibitor STI571 for 4-h reversed changes in expression of some of these cytoskeletal proteins. Correspondingly, BCR/ABL-transfected cells were less responsive to chemotactic and chemokinetic stimuli than non-transfected cells and TEL/PDGFRbeta-transfected Ba/F3 cells. Decreased motile response was reversed by a 16-h treatment with STI571. A phosphoprotein-specific gel stain was used to identify TEL/PDGFRbeta and BCR/ABL-mediated changes in the phosphoproteome. These included changes on Crkl, Ras-GAP-binding protein 1, and for BCR/ABL, cytoskeletal proteins such as tubulin, and Nedd5. Decreased phosphorylation of Rho-GTPase dissociation inhibitor (Rho GDI) was also observed in BCR/ABL-transfected cells. This results in the activation of the Rho pathway, and treatment of cells with Y27632, an inhibitor of Rho kinase, inhibited DNA synthesis in BCR/ABL-transfected Ba/F3 cells but not TEL/PDGFRbeta-expressing cells. Expression of a dominant-negative RhoA inhibited both DNA synthesis and transwell migration, demonstrating the significance of this pathway in BCR/ABL-mediated transformation.
Affiliation:
Faculty of Medical and Human Sciences, University of Manchester.
Citation:
Global effects of BCR/ABL and TEL/PDGFRbeta expression on the proteome and phosphoproteome: identification of the Rho pathway as a target of BCR/ABL. 2005, 280 (8):6316-26 J. Biol. Chem.
Journal:
The Journal of Bological Chemistry
Issue Date:
25-Feb-2005
URI:
http://hdl.handle.net/10541/75636
DOI:
10.1074/jbc.M410598200
PubMed ID:
15569670
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorUnwin, Richard D-
dc.contributor.authorSternberg, David W-
dc.contributor.authorLu, Yuning-
dc.contributor.authorPierce, Andrew-
dc.contributor.authorGilliland, D Gary-
dc.contributor.authorWhetton, Anthony D-
dc.date.accessioned2009-07-24T15:29:37Z-
dc.date.available2009-07-24T15:29:37Z-
dc.date.issued2005-02-25-
dc.identifier.citationGlobal effects of BCR/ABL and TEL/PDGFRbeta expression on the proteome and phosphoproteome: identification of the Rho pathway as a target of BCR/ABL. 2005, 280 (8):6316-26 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid15569670-
dc.identifier.doi10.1074/jbc.M410598200-
dc.identifier.urihttp://hdl.handle.net/10541/75636-
dc.description.abstractMany leukemic oncogenes form as a consequence of gene fusions or mutation that result in the activation or overexpression of a tyrosine kinase. To identify commonalities and differences in the action of two such kinases, breakpoint cluster region (BCR)/ABL and TEL/PDGFRbeta, two-dimensional gel electrophoresis was employed to characterize their effects on the proteome. While both oncogenes affected expression of specific proteins, few common effects were observed. A number of proteins whose expression is altered by BCR/ABL, including gelsolin and stathmin, are related to cytoskeletal function whereas no such changes were seen in TEL/PDGFRbeta-transfected cells. Treatment of cells with the kinase inhibitor STI571 for 4-h reversed changes in expression of some of these cytoskeletal proteins. Correspondingly, BCR/ABL-transfected cells were less responsive to chemotactic and chemokinetic stimuli than non-transfected cells and TEL/PDGFRbeta-transfected Ba/F3 cells. Decreased motile response was reversed by a 16-h treatment with STI571. A phosphoprotein-specific gel stain was used to identify TEL/PDGFRbeta and BCR/ABL-mediated changes in the phosphoproteome. These included changes on Crkl, Ras-GAP-binding protein 1, and for BCR/ABL, cytoskeletal proteins such as tubulin, and Nedd5. Decreased phosphorylation of Rho-GTPase dissociation inhibitor (Rho GDI) was also observed in BCR/ABL-transfected cells. This results in the activation of the Rho pathway, and treatment of cells with Y27632, an inhibitor of Rho kinase, inhibited DNA synthesis in BCR/ABL-transfected Ba/F3 cells but not TEL/PDGFRbeta-expressing cells. Expression of a dominant-negative RhoA inhibited both DNA synthesis and transwell migration, demonstrating the significance of this pathway in BCR/ABL-mediated transformation.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshCell Line-
dc.subject.meshCell Transformation, Neoplastic-
dc.subject.meshElectrophoresis, Gel, Two-Dimensional-
dc.subject.meshFusion Proteins, bcr-abl-
dc.subject.meshGene Expression Profiling-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshMice-
dc.subject.meshOncogene Proteins, Fusion-
dc.subject.meshPhosphoproteins-
dc.subject.meshPiperazines-
dc.subject.meshProteome-
dc.subject.meshPyrimidines-
dc.subject.meshTransfection-
dc.titleGlobal effects of BCR/ABL and TEL/PDGFRbeta expression on the proteome and phosphoproteome: identification of the Rho pathway as a target of BCR/ABL.en
dc.typeArticleen
dc.contributor.departmentFaculty of Medical and Human Sciences, University of Manchester.en
dc.identifier.journalThe Journal of Bological Chemistryen

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