The dimerization property of glutathione S-transferase partially reactivates Bcr-Abl lacking the oligomerization domain.
Bcr-Abl oncoproteins are responsible for the pathogenesis of human leukemias with a reciprocal chromosome translocation t(9;22). The amino-terminal Bcr sequence has a potential to form a homotetramer (tetramer domain), and destructions of the tetramer domain cause a complete loss of biological activities in Bcr-Abl. Here we show that Bcr-Abl in which the tetramer domain is replaced with glutathione S-transferase (GST) with a dimerizing ability (GST/Bcr-Abl-(Delta1-160)) can no longer induce an interleukin-3 (IL-3) independence in Ba/F3 cells or transform mouse bone marrow cells but still retains by 30-40% the ability to transform Rat1 cells. Compared with the wild type Bcr-Abl, autophosphorylation of GST/Bcr-Abl-(Delta1-160) in vivo was reduced by more than 50%. The Grb-2 binding to GST/Bcr-Abl-(Delta1-160) was 50% reduced in Rat1 cells and undetectable in Ba/F3 cells. In Rat1 cells expressing GST/Bcr-Abl-(Delta1-160), phosphotyrosine contents of p62 and Shc were 70% decreased.
Maru
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Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan.
Afar
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Witte
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Shibuya
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D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001854:Bone Marrow Cells; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D005982:Glutathione Transferase / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins; D013329:Structure-Activity Relationship
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; C495950:Grb2 protein, rat; D046911:Macromolecular Substances; D011506:Proteins; D011993:Recombinant Fusion Proteins; D019000:Phosphotyrosine; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl