The Dbl homology domain of BCR is not a simple spacer in P210BCR-ABL of the Philadelphia chromosome.
The Dbl homology (DH) domain of BCR in P210BCR-ABL (P210/WT) has been thought to have a negative effect on the activation of BCR-ABL because P185BCR-ABL, in which this region is physically deleted, has stronger biochemical and biological activities. To study the role of the DH domain of BCR in the background of P210/WT, the region was replaced with homologous sequences derived from Dbl (P210/Dbl) or CDC24 (P210/CDC24) or with irrelevant sequences from LacZ (P210/LacZ) or luciferase (P210/Luci). Surprisingly, the abilities to transform Rat1 cells or mouse bone marrow cells and induce growth factor independence in interleukin 3-dependent mouse Ba/F3 cells were retained only in P210/Dbl. However, even P210/Dbl could not achieve the wild type level of surviving potential against genotoxins in Rat1 cells and in Ba/F3 cells. Activation of Akt correlated with the biological changes in Rat1 cells but did not correlate with the biological changes in Ba/F3 cells. The DH domain was not tyrosine-phosphorylated in vitro, nor could we find any differences in peptide mapping between in vitro phosphorylated P210/WT and P210/Dbl. Although functions of the DH domain remain to be discovered, we propose that the DH domain makes positive contributions to P210BCR-ABL.
Kin
Y
Y
Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan.
Li
G
G
Shibuya
M
M
Maru
Y
Y
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D002460:Cell Line; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000235:genetics*; D017353:Gene Deletion; D020662:Guanine Nucleotide Exchange Factors; D007763:Lac Operon; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010677:Philadelphia Chromosome; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics*; D051381:Rats; D013997:Time Factors; D014170:Transformation, Genetic; D014443:Tyrosine / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; C512843:Mcf2 protein, mouse; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D008156:Luciferases; D016044:Fusion Proteins, bcr-abl