The v-abl tyrosine kinase negatively regulates NF-kappa B/Rel factors and blocks kappa gene transcription in pre-B lymphocytes.

Klug, Christopher A.; Gerety, Sheila J.; Shah, Pratik; Chen, Yunn-Yi; Rice, Nancy R.; Rosenberg, Naomi; Singh, Harinder

doi:10.1101/gad.8.6.678

Cited by 80 publications

(49 citation statements)

References 44 publications

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“…This result is of interest since REL/NF-kB activity is targeted by numerous oncogenes and its deregulation is involved in malignant transformation (Gilmore et al, 1996). Moreover NF-kB activity is targeted by v-abl, its down regulation allows transformation of B lineage precursors (Kerr, 1994;Klug et al, 1994). The dierence with our results can be attributed to the fundamental dierences between BCR ± ABL and v-abl regarding to their structure, their cellular localization, their transforming potential in ®broblasts, their interaction with signaling proteins and the induced disease in vivo (Cook, 1982;Daley et al, 1987Daley et al, , 1990McWhirter and Witte, 1991;McWhirter et al, 1993;Reuther et al, 1994;Varticovski et al, 1991).…”

Section: Discussionmentioning

confidence: 65%

Activation of p65 NF-κB protein by p210BCR – ABL in a myeloid cell line (P210BCR – ABL activates p65 NF-κB)

1997

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The chimeric tyrosine kinase p210 BCR ± 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 p210 BCR ± 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 eect of p210 BCR ± ABL expression on NF-kB activity in DA1 cells (an IL-3-dependent murine myeloid progenitor cell line). A speci®c stimulation of NF-kB activity by kinase-active wild-type p210 BCR ± ABL has been evidenced by transcriptional activation assays. Electrophoretic mobility supershift assays revealed the presence of p65 protein (RelA) DNA binding activity in p210 BCR ± 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 p210 BCR ± ABL transfected cells failed to survive after IL-3 removal. Moreover, inhibition of cellular growth was shown following treatment of p210 BCR ± ABL transformed DA1 cells by p65 antisense oligonucleotides. This study suggests that p65 NF-kB may be an eector for p210 BCR ± ABL and probably contributes to its induced transformation process.

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Section: Discussionmentioning

confidence: 65%

Activation of p65 NF-κB protein by p210BCR – ABL in a myeloid cell line (P210BCR – ABL activates p65 NF-κB)

1997

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“…When cultured at the nonpermissive temperature, these ts-abl cells exhibit levels of nuclear NF-B, RAG expression, and VJ rearrangement that are comparable to those observed in bone marrow pre-B cells (15,16). By using a dominant mutant of IB, we have shown previously that the NF-B signaling pathway is critically required for activation of VJ rearrangement in ts-abl cells (12).…”

Section: Discussionmentioning

confidence: 99%

“…Inactivation of the temperature-sensitive v-abl oncogene in these cells (ts-abl cells) induces levels of RAG gene expression, NF-B, and IgL rearrangement that are comparable to those observed in vivo (12,15,16). We generated transfectants of the ts-abl line that stably express a mutant form of the NF-B inhibitory protein IB␣, termed IB⌬N.…”

Section: Nf-b Regulates Ig Gene Rearrangementmentioning

confidence: 99%

“…The 103/BCL-2/4 pre-B cell line is conditionally transformed with a temperature-sensitive (ts) mutant of the v-abl oncogene (15,16). Stable transfectants of ts-abl expressing a dominant inhibitor of NF-B, termed IB⌬N (⌬N.1, ⌬N.7), and a control line expressing the histidinol resistance gene (WT.24) have been described previously (12).…”

Section: Cell Lines and Culturementioning

confidence: 99%

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Transcription Factor NF-κB Regulates Igλ Light Chain Gene Rearrangement

Bendall

Sikes

Oltz

2001

The Journal of Immunology

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The tissue- and stage-specific assembly of Ig and TCR genes is mediated by a common V(D)J recombinase complex in precursor lymphocytes. Directed alterations in the accessibility of V, D, and J gene segments target the recombinase to specific Ag receptor loci. Accessibility within a given locus is regulated by the functional interaction of transcription factors with cognate enhancer elements and correlates with the transcriptional activity of unrearranged gene segments. As demonstrated in our prior studies, rearrangement of the Igκ locus is regulated by the inducible transcription factor NF-κB. In contrast to the Igκ locus, known transcriptional control elements in the Igλ locus lack functional NF-κB binding sites. Consistent with this observation, the expression of assembled Igλ genes in mature B cells has been shown to be NF-κB independent. Nonetheless, we now show that specific repression of NF-κB inhibits germline transcription and recombination of Igλ gene segments in precursor B cells. Molecular analyses indicate that the block in NF-κB impairs Igλ rearrangement at the level of recombinase accessibility. In contrast, the activities of known Igλ promoter and enhancer elements are unaffected in the same cellular background. These findings expand the range of NF-κB action in precursor B cells beyond Igκ to include the control of recombinational accessibility at both L chain loci. Moreover, our results strongly suggest the existence of a novel Igλ regulatory element that is either directly or indirectly activated by NF-κB during the early stages of B cell development.

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“…During studies on the v-Abl-induced arrest of B-cell differentiation it was found that v-Abl negatively regulates NF-kB transcription factors by an unidentified post-translational mechanism (Klug et al, 1994). NF-kB produces multiple biological effects, affecting cell proliferation, survival and death (Foo and Nolan, 1999;Gutteridge et al, 1999;Hinz et al, 1999).…”

Section: Signal Transduction Pathways Activated By V-ablmentioning

confidence: 99%