Unique Pattern of Overexpression of Raf-1 Kinase Inhibitory Protein in Its Inactivated Phosphorylated Form in Human Multiple Myeloma.
Unique Pattern of Overexpression of Raf-1 Kinase Inhibitory Protein in Its Inactivated Phosphorylated Form in Human Multiple Myeloma.
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DOI：
10.1615/forumimmundisther.v2.i2.90
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发表时间：
2011-04-01
期刊：
影响因子：
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通讯作者：
Bonavida B
中科院分区：
文献类型：
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作者：
Baritaki S;Huerta-Yepez S;Cabrava-Haimandez MD;Sensi M;Canevari S;Libra M;Penichet M;Chen H;Berenson JR;Bonavida B
多发性骨髓瘤（MM）是第二常见的血液学和无法治愈的恶性肿瘤浆细胞在骨髓低增殖活性。MM患者最初对常规治疗有反应，然而，许多患者产生耐药性并发生复发。我们已经确定RKIP是一种新的基因产物，与其他研究的肿瘤和正常骨髓相比，RKIP在MM细胞系和MM组织中存在差异过表达。这种过表达在很大程度上是RKIP在Ser153位点磷酸化的无活性形式（p-Ser153 RKIP）。与RKIP相反，p-Ser153 RKIP缺乏抑制MAPK信号通路的能力。在携带人MM异种移植物LAGλ-1B的小鼠模型中，进一步验证了p-Ser153 RKIP在MM细胞系和MM组织中的过表达。来自数据库的生物信息学分析支持与正常浆细胞相比，MM中RKIP mRNA表达增加。在这些数据库中，MM中的高RKIP水平也与非超二倍体状态和IgH易位的存在相关，这些参数通常显示出更积极的临床特征，无论治疗如何，患者的生存期都更短。由于RKIP的表达同时调控NF-κB和MAPK的存活通路，因此“失活”p-Ser153 RKIP在MM中的过表达可能通过组成性激活存活通路和下游抗凋亡基因产物的转录，对MM的整体细胞存活/抗凋亡表型和耐药起积极作用。RKIP和p-Ser153 RKIP在MM中的过表达是文献中首次证实的，因为在大多数肿瘤组织中RKIP的表达非常低，而p-Ser153 RKIP的表达要低得多。MM中活性RKIP水平与非活性p-Ser153 RKIP水平之间的关系可能具有预后意义，RKIP活性的调节可能是治疗干预的目标。
Multiple myeloma (MM) is the second most common hematological and incurable malignancy of plasma cells with low proliferative activity in the bone marrow. MM patients initially respond to conventional therapy, however, many develop resistance and recurrences occur. We have identified RKIP as a novel gene product that is differentially overexpressed in MM cell lines and MM tissues compared to other studied tumors and normal bone marrow. This overexpression consisted, in large part, of a phosphorylated inactive form of RKIP at Ser153 (p-Ser153 RKIP). In contrast to RKIP, p-Ser153 RKIP lacks its ability to inhibit the MAPK signaling pathway. The overexpression of p-Ser153 RKIP in MM cell lines and MM tissues was further validated in a mouse model carrying a human MM xenograft, namely, LAGλ-1B. Bioinformatic analyses from databases support the presence of increased RKIP mRNA expression in MM compared to normal plasma cells. In these databases, high RKIP levels in MM are also correlated with the nonhyperdiploid status and the presence of IgH translocations, parameters that generally display more aggressive clinical features and shorter patients’ survival irrespective of the treatment. Since RKIP expression regulates both the NF-κB and MAPK survival pathways, the overexpression of “inactive” p-Ser153 RKIP in MM might contribute positively to the overall cell survival/antiapoptotic phenotype and drug resistance of MM through the constitutive activation of survival pathways and downstream the transcription of anti-apoptotic gene products. The overexpression of RKIP and p-Ser153 RKIP in MM is the first demonstration in the literature, since in most tumor tissues the expression of RKIP is very low and the expression of p-Ser153 RKIP is much lower. The relationship between the levels of active RKIP and inactive p-Ser153 RKIP in MM may be of prognostic significance, and the regulation of RKIP activity may be a target for therapeutic intervention.