Evidence for a role of NF-kappaB in the survival of hematopoietic cells mediated by interleukin 3 and the oncogenic TEL/platelet-derived growth factor receptor beta fusion protein.
Interleukin 3 (IL-3) and other hematopoietic cytokines transduce signals that stimulate DNA synthesis and cell survival. In certain chronic myelomonocytic leukemias, a TEL/platelet-derived growth factor receptor beta (PDGFRbeta) fusion protein is produced as a consequence of the t(5;12) translocation. It contains the amino terminus of the transcription factor TEL fused to the transmembranous and cytoplasmic domains of the PDGFRbeta. It is oncogenic as it substitutes for IL-3, thus promoting cell growth and preventing apoptotic cell death. The mechanism by which TEL/PDGFRbeta generates survival signals remains undefined. Here, we report that both IL-3 and TEL/PDGFRbeta initiate a signaling cascade that leads to the activation of the transcriptional factor NF-kappaB. In fact, either cytokine deprivation of IL-3-dependent Ba/F3 cells or exposure of TEL/PDGFRbeta-expressing cells to the specific inhibitor of the PDGFR tyrosine kinase, CGP53716, caused a strong decrease in NF-kappaB activity followed by extensive cell death. Further, treatment with the proteasome inhibitor Z-IE(O-t-Bu)A-leucinal suppressed IL-3 and TEL/PDGFRbeta-dependent survival. The same result was seen upon overexpression of an unphosphorylable form of IkappaBalpha. Because both conditions inactivate NF-kappaB by preventing its translocation into the nucleus, that process seems to be essential for cell survival in response to IL-3 and TEL/PDGFRbeta. Moreover, overexpression of a dominant-negative mutant of the protooncogene c-Myc, a downstream target of NF-kappaB, had a similar effect. We conclude that NF-kappaB plays an important role in maintaining cell survival in response to IL-3 and TEL/PDGFRbeta and that c-Myc may be a downstream effector mediating this effect.
Besançon
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Institut National de la Sante et de la Recherche Medicale, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571, Paris Cédex 12, France.
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Gespach
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Cayre
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Bourgeade
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D007377:Interleukin-3 / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000494:pharmacology*; D050783:Proto-Oncogene Proteins c-ets; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics*; D012097:Repressor Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D011725:Pyridines; D011743:Pyrimidines; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D012097:Repressor Proteins; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein; C092972:CGP 53716