title: Inactivation of NF-kappaB-dependent cell survival, a novel mechanism for the proapoptotic function of c-Abl.
abstract: 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.
authors.affiliation: Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Kawai
authors.forename: Linghu
authors.initials: L
authors.lastname: Nie
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D005347:Fibroblasts; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology; D016313:Genes, abl; D006801:Humans; D020672:I-kappa B Proteins; D007668:Kidney; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D019000:Phosphotyrosine / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011993:Recombinant Fusion Proteins; D000072000:NF-KappaB Inhibitor alpha; D010768:Phosphoserine; D019000:Phosphotyrosine; D004317:Doxorubicin; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl