Activation of p65 NF-kappaB protein by p210BCR-ABL in a myeloid cell line (P210BCR-ABL activates p65 NF-kappaB).
The chimeric tyrosine kinase p210BCR-ABL is involved in the pathogenesis of chronic myelogenous leukemia. It transforms immature hematopoietic cells in vitro and abrogates IL-3-dependent growth. The mechanisms by which p210BCR-ABL mediates its oncogenicity are not well elucidated. Identifying transcription factors targeted by the chimeric protein may help to clarify these mechanisms. We have analysed the effect of p210BCR-ABL expression on NF-kappaB activity in DA1 cells (an IL-3-dependent murine myeloid progenitor cell line). A specific stimulation of NF-kappaB activity by kinase-active wild-type p210BCR-ABL has been evidenced by transcriptional activation assays. Electrophoretic mobility supershift assays revealed the presence of p65 protein (RelA) DNA binding activity in p210BCR-ABL transformed DA1 cells but not in parental DA1 cells. Activation of RelA in transformed DA1 cells may occur by protein stabilization. Experiments using oligonucleotides antisense to RelA showed that p210BCR-ABL transfected cells failed to survive after IL-3 removal. Moreover, inhibition of cellular growth was shown following treatment of p210BCR-ABL transformed DA1 cells by p65 antisense oligonucleotides. This study suggests that p65 NF-kappaB may be an effector for p210BCR-ABL and probably contributes to its induced transformation process.
Hamdane
M
M
INSERM U124, Onco-Hématologie Moléculaire, Institut de Recherches sur le Cancer de Lille, France.
David-Cordonnier
M H
MH
D'Halluin
J C
JC
D000818:Animals; D001854:Bone Marrow Cells; D002135:Calcium-Binding Proteins; D002460:Cell Line; D002461:Cell Line, Transformed; D016044:Fusion Proteins, bcr-abl / Q000494:pharmacology*; D005786:Gene Expression Regulation; D007377:Interleukin-3 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense; D009857:Oncogenes; D012333:RNA, Messenger / Q000032:analysis; D050863:Synaptotagmin I; D050857:Synaptotagmins; D051996:Transcription Factor RelA
D002135:Calcium-Binding Proteins; D007377:Interleukin-3; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D050863:Synaptotagmin I; D051996:Transcription Factor RelA; D050857:Synaptotagmins; D016044:Fusion Proteins, bcr-abl