RT Journal Article ID 5143b84d465315b5 A1 Baritaki, Stavroula A1 Huerta-Yepez, Sara A1 Cabrava-Haimandez, Ma da Lourdas A1 Sensi, Marialuisa A1 Canevari, Silvana A1 Libra, Massimo A1 Penichet, Manuel A1 Chen, Haiming A1 Berenson, James R. A1 Bonavida, Benjamin T1 Unique Pattern of Overexpression of Raf-1 Kinase Inhibitory Protein in Its Inactivated Phosphorylated Form in Human Multiple Myeloma JF Onco Therapeutics JO OT YR 2011 FD 2011-02-17 VO 2 IS 2 SP 179 OP 188 K1 NF-kB K1 Raf-1 kinase inhibitor protein (RKIP) K1 apoptosis K1 multiple myeloma AB 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. PB Begell House LK https://www.dl.begellhouse.com/journals/2c6306423483e001,7fbbfe03365afb86,5143b84d465315b5.html