title: Transformation of interleukin-3-dependent cells without participation of Stat5/bcl-xL: cooperation of akt with raf/erk leads to p65 nuclear factor kappaB-mediated antiapoptosis involving c-IAP2.
abstract: Tyrosine kinase oncogenes such as p210BCR-ABL activate multiple signal pathways. As a result, it is difficult to infer the functional relevance of a pathway acting alone or in cooperation with another. One or 2 second-tier kinases represented in the p21ras and phosphatidylinositol-3-kinase (PI-3-kinase) pathways (activated RafCAAX and gag-akt, respectively) were expressed in parental H7 interleukin-3 (IL-3)-dependent myeloid cells. IL-3-dependent cells served, independently, as recipients of p210BCR-ABL, which activated p21ras and PI-3-kinase pathways, including raf/erk and akt, respectively, en route to transformation. By contrast, neither RafCAAX nor gag-akt when expressed in parental cells in isolation produced factor-independent cells. On the other hand, H7 cells expressing both RafCAAX and gag-akt (H7gag-akt/RafCAAX) were transformed. Such transformation in H7gag-akt/RafCAAX was accomplished in the absence of active versions of Shc or cbl, and there was no evidence of Stat activity and only modest amounts of bcl-xL, a Stat5 transcriptional target protein, all of which characterized the cells transformed by BCR-ABL. However, H7gag-akt/RafCAAX cells and H7BCR-ABL cells cultured in the absence of IL-3 shared strikingly increased p65 nuclear factor kappaB (NFkappaB) activity. Treatment of cells with a specific NFkappaB inhibitor, parthenolide, led to loss of NFkappaB activity and down-regulation of antiapoptotic c-IAP2. In cells with only gag-akt/RafCAAX, this was sufficient to allow polyADP ribosyltransferase (PARP)-degradative apoptosis, but in cells with p210BCR-ABL, apoptosis was blocked, possibly by a Stat5/bcl-xL-dependent mechanism. Therefore, one hematopoietic antiapoptotic program, among others, available to certain tyrosine kinase oncogenes involves a cooperative response between raf/erk and akt, unambiguous components of p21ras and PI-3-kinase pathways, to induce p65 NFkappaB and c-IAP2.
authors.affiliation: Walther Cancer Institute and Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine and VA Medical Center, Indianapolis, IN 46202, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Gelfanov
authors.forename: G S
authors.initials: GS
authors.lastname: Burgess
authors.forename: S
authors.initials: S
authors.lastname: Litz-Jackson
authors.forename: A J
authors.initials: AJ
authors.lastname: King
authors.forename: M S
authors.initials: MS
authors.lastname: Marshall
authors.forename: H
authors.initials: H
authors.lastname: Nakshatri
authors.forename: H S
authors.initials: HS
authors.lastname: Boswell
mesh_terms: D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007377:Interleukin-3 / Q000276:immunology*; D007951:Leukemia, Myeloid; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013539:Simian virus 40 / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D007377:Interleukin-3; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D016044:Fusion Proteins, bcr-abl; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases