Inactivation of NF-kappaB-dependent cell survival, a novel mechanism for the proapoptotic function of c-Abl.
Using a system that expresses a constitutively kinase-active c-Abl protein [c-Abl(KA)], we identified the protein IkappaBalpha as a novel substrate of c-Abl. This kinase-substrate relationship is not only confirmed at the level of endogenous proteins but is also supported by a physical interaction between the two proteins. Interestingly, the association ... of c-Abl with IkappaBalpha, which is detectable in the form of nonphosphorylated proteins, is remarkably enhanced by an inducible binding of tyrosine-phosphorylated IkappaBalpha to the c-Abl SH2 domain. In contrast to the serine 32/34 phosphorylation that triggers ubiquitination and degradation of IkappaBalpha, c-Abl-mediated phosphorylation at tyrosine 305 is associated with an increase of the IkappaBalpha protein stability. Significantly, this activity is not shared by the oncogenic Bcr-Abl, because it is unique to the nuclear c-Abl. We also demonstrate that c-Abl targets the nuclear subpopulation of IkappaBalpha for phosphorylation and induces it to accumulate in the nucleus. As a consequence, NF-kappaB transcription activity is abolished, leading to an increased cellular sensitivity to the induction of apoptosis. The functional importance of c-Abl-mediated IkappaBalpha phosphorylation is highlighted by a loss of response of the IkappaBalpha(Y305F) protein to c-Abl-mediated regulation. Using cells expressing the c-Abl(KA) protein under the control of an inducible promoter, we demonstrate inactivation of the NF-kappaB-dependent cell survival pathway as one of the mechanisms for c-Abl-mediated apoptosis.
Mesh Terms:
Animals, Apoptosis, Cell Line, Cell Nucleus, DNA-Binding Proteins, Doxorubicin, Fibroblasts, Fusion Proteins, bcr-abl, Genes, abl, Humans, I-kappa B Proteins, Kidney, Mice, Mice, Knockout, NF-kappa B, Phosphorylation, Phosphoserine, Phosphotyrosine, Protein Processing, Post-Translational, Protein Transport, Proto-Oncogene Proteins c-abl, Recombinant Fusion Proteins, Structure-Activity Relationship, Transfection, Tumor Cells, Cultured, src Homology Domains
Animals, Apoptosis, Cell Line, Cell Nucleus, DNA-Binding Proteins, Doxorubicin, Fibroblasts, Fusion Proteins, bcr-abl, Genes, abl, Humans, I-kappa B Proteins, Kidney, Mice, Mice, Knockout, NF-kappa B, Phosphorylation, Phosphoserine, Phosphotyrosine, Protein Processing, Post-Translational, Protein Transport, Proto-Oncogene Proteins c-abl, Recombinant Fusion Proteins, Structure-Activity Relationship, Transfection, Tumor Cells, Cultured, src Homology Domains
Mol. Cell. Biol.
Date: Sep. 01, 2002
PubMed ID: 12167702
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