Faculty Collaboration Database

The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival. Leukemia 2013 Feb;27(2):441-50

Date

07/10/2012

Pubmed ID

22772059

Pubmed Central ID

PMC4047128

DOI

10.1038/leu.2012.185

Scopus ID

2-s2.0-84873570632 (requires institutional sign-in at Scopus site)   44 Citations

Abstract

Y-box binding protein 1 (YB-1) functions as a translational regulator and has been suggested to elevate MYC mRNA translation via an internal ribosome entry segment (IRES) point mutation in multiple myeloma (MM). We show that YB-1-mediated translation of MYC mRNA occurs independently of the reported IRES mutation, as 87 MM patients (n=88) and all tested human MM cell lines (HMCLs) were negative for the mutation. We show for the first time that positive MYC staining predicts YB-1 co-expression in malignant plasma cells and YB-1/MYC co-expression increases from 30% in medullary to 70% in extramedullary MM. YB-1 knockdown in HMCLs reduced both MYC protein levels and MYC mRNA in the polysomal fraction, providing a mechanism by which YB-1 controls MYC translation. MYC transcription of YB-1 is demonstrated in HMCLs as MYC knockdown resulted in reduced YB-1 protein and mRNA levels. Furthermore, MYC activation in non-malignant mouse embryonic fibroblasts (MEFs) increased YB-1 mRNA, clearly indicating that MYC drives YB-1 transcription. Importantly, perturbation of the MYC/YB-1 oncogenic circuit leads to apoptosis in HMCLs. Here, we demonstrate that these two proteins co-regulate each other via combined transcriptional/translational activity establishing their pivotal role in MM cell survival. We therefore suggest that targeting the YB-1/mRNA interaction provides a new strategy for MM drug development.

Author List

Bommert KS, Effenberger M, Leich E, Küspert M, Murphy D, Langer C, Moll R, Janz S, Mottok A, Weissbach S, Rosenwald A, Bargou R, Bommert K

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Biomarkers, Tumor
Blotting, Western
Cell Proliferation
Cells, Cultured
Embryo, Mammalian
Fibroblasts
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Immunoenzyme Techniques
Mice
Multiple Myeloma
Oligonucleotide Array Sequence Analysis
Point Mutation
Polyribosomes
Protein Biosynthesis
Proto-Oncogene Proteins c-myc
RNA, Messenger
RNA, Small Interfering
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Y-Box-Binding Protein 1