An active v-abl protein tyrosine kinase blocks immunoglobulin light-chain gene rearrangement.
Lymphoid cells transformed by Abelson murine leukemia virus have provided one of the classic models for study of early B-cell development and immunoglobulin rearrangement. Most of these cells have rearranged their heavy-chain locus but not their light chain genes, suggesting that an active v-abl protein interferes with this differentiation step. To test this hypothesis, light-chain gene structure was examined in pre-B cells transformed by temperature-sensitive mutants of the Abelson virus and in derivatives that survive at the nonpermissive temperature because they express a human BCL-2 gene. Our studies reveal that inactivation of the v-abl protein tyrosine kinase triggers high-frequency rearrangement of kappa and lambda light-chain genes. These events are accompanied by marked increases in the expression of RAG-1 and RAG-2 RNAs. These increases occur in the absence of protein synthesis but are dependent on inactivation of the v-abl protein tyrosine kinase. As documented in the accompanying paper (Klug et al., this issue), an active v-abl protein also suppresses the activity of NF-kappa B/rel and expression controlled by the kappa intron enhancer. Together these data demonstrate that the v-abl protein specifically interferes with light-chain gene rearrangement by suppressing at least two pathways essential for this stage of B-cell differentiation and suggest that tyrosine phosphorylation is important in regulating RAG gene expression.
Chen
Y Y
YY
Immunology Graduate Program, Tufts University School of Medicine, Boston, Massachusetts 02111.
Wang
L C
LC
Huang
M S
MS
Rosenberg
N
N
D000011:Abelson murine leukemia virus / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002461:Cell Line, Transformed; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D018398:Homeodomain Proteins; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D019426:Integrases; D007438:Introns; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism; D009687:Nuclear Proteins; D016374:Oncogene Proteins v-abl / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; D045522:Recombinases
D017931:DNA Primers; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007147:Immunoglobulin Light Chains; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D016328:NF-kappa B; D009687:Nuclear Proteins; D016374:Oncogene Proteins v-abl; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D045522:Recombinases; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D011505:Protein-Tyrosine Kinases; D004254:DNA Nucleotidyltransferases; D019426:Integrases; C115006:integron integrase IntI1