The v-abl tyrosine kinase negatively regulates NF-kappa B/Rel factors and blocks kappa gene transcription in pre-B lymphocytes.
Transformation of B-lineage precursors by the Abelson murine leukemia virus appears to arrest development at the pre-B stage. Abelson-transformed pre-B cell lines generally retain transcriptionally inactive, unrearranged immunoglobulin kappa alleles. We demonstrate that nontransformed pre-B cells expanded from the mouse bone marrow efficiently transcribe unrearranged kappa alleles. In addition, they contain activated complexes of the NF-kappa B/Rel transcription factor family, in contrast with their Abelson-transformed counterparts. Using conditionally transformed pre-B cell lines, we show that the v-abl viral transforming protein, a tyrosine kinase, blocks germ-line kappa gene transcription and negatively regulates NF-kappa B/Rel activity. An active v-abl kinase specifically inhibits the NF-kappa B/Rel-dependent kappa intron enhancer, which is implicated in promoting both transcription and rearrangement of the kappa locus. v-abl inhibits the activated state of NF-kappa B/Rel complexes in a pre-B cell via a post-translational mechanism that results in increased stability of the inhibitory subunit I kappa B alpha. This analysis suggests a molecular pathway by which v-abl inhibits kappa locus transcription and rearrangement.
Klug
C A
CA
Howard Hughes Medical Institute, University of Chicago, Illinois 60637.
Gerety
S J
SJ
Shah
P C
PC
Chen
Y Y
YY
Rice
N R
NR
Rosenberg
N
N
Singh
H
H
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D005803:Genes, Immunoglobulin; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015345:Oligonucleotide Probes; D016374:Oncogene Proteins v-abl / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D007145:Immunoglobulin kappa-Chains; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D016374:Oncogene Proteins v-abl; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases