Evidence for a role of NF-κB in the survival of hematopoietic cells mediated by interleukin 3 and the oncogenic TEL/platelet-derived growth factor receptor β fusion protein
Evidence for a role of NF-κB in the survival of hematopoietic cells mediated by interleukin 3 and the oncogenic TEL/platelet-derived growth factor receptor β fusion protein
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DOI：
10.1073/pnas.95.14.8081
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发表时间：
1998-07-07
影响因子：
11.1
通讯作者：
Bourgeade, MF
中科院分区：
文献类型：
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作者：
Besançon, F;Atfi, A;Bourgeade, MF
白细胞介素3（IL-3）和其他造血细胞因子是刺激DNA合成和细胞存活的信号。在某些慢性粒单核细胞白血病中，由于t（5;12）易位而产生TEL/血小板衍生生长因子受体β（PDGFR β）融合蛋白。它含有与PDGFR β的跨膜和胞质结构域融合的转录因子TEL的氨基末端。它是致癌的，因为它取代IL-3，从而促进细胞生长和防止凋亡细胞死亡。TEL/PDGFR β产生存活信号的机制仍不清楚。在此，我们报道IL-3和TEL/PDGFR β均启动导致转录因子NF-κ B B活化的信号级联。事实上，IL-3依赖性Ba/F3细胞的细胞因子剥夺或TEL/PDGFR β表达细胞暴露于PDGF 1 R酪氨酸激酶的特异性抑制剂CGP 53716，引起NF-κ B活性的强烈降低，随后是广泛的细胞死亡。此外，用蛋白酶体抑制剂Z-IE（O-t-Bu）A-亮氨酸治疗抑制IL-3和TEL/PDGFR β依赖性存活。在I κ B α的非磷酸化形式过表达时也观察到相同的结果。因为这两种情况都通过阻止NF-κ B易位到细胞核中而使其活化，所以该过程似乎对于响应IL-3和TEL/PDGFR β的细胞存活是必不可少的。此外，原癌基因c-Myc的显性负突变体（NF-κ B的下游靶基因）的过表达具有类似的效果。我们的结论是，NF-κ B B在维持细胞存活响应IL-3和TEL/PDGFR β和c-Myc可能是介导这种效果的下游效应器中起着重要作用。
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 (PDGFR beta) 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 PDGFR beta. It is oncogenic as it substitutes for IL-3, thus promoting cell growth and preventing apoptotic cell death. The mechanism by which TEL/PDGFR beta generates survival signals remains undefined, Here, we report that both IL-3 and TEL/PDGFR beta initiate a signaling cascade that leads to the activation of the transcriptional factor NF-kappa B, In fact, either cytokine deprivation of IL3-dependent Ba/F3 cells or exposure of TEL/PDGFR beta-expressing cells to the specific inhibitor of the PDGFlR tyrosine kinase, CGP53716, caused a strong decrease in NF-kappa B activity followed by extensive cell death. Further, treatment with the proteasome inhibitor Z-IE(O-t-Bu)A-leucinal suppressed IL-3 and TEL/PDGFR beta-dependent survival. The same result,vas seen upon overexpression of an unphosphorylable form of I kappa B alpha. Because both conditions inactivate NF-kappa B by preventing its translocation into the nucleus, that process seems to be essential for cell survival in response to IL-3 and TEL/PDGFR beta, Moreover, overexpression of a dominant-negative mutant of the protooncogene c-Myc, a downstream target of NF-kappa B, had a similar effect. We conclude that NF-kappa B plays an important role in maintaining cell survival in response to IL-3 and TEL/PDGFR beta and that c-Myc may be a downstream effector mediating this effect.