YB-1 facilitates basal and 5-fluorouracil-inducible expression of the human major vault protein (MVP) gene

Abstract

Vaults have been suggested to play a direct role in multidrug resistance (MDR) to anticancer drugs. The human major vault protein (MVP) also known as lung resistance-related protein (LRP) represents the predominant component of vaults that may be involved in the defense against xenobiotics. Here, we demonstrate that besides MDR-related cytostatics, also the non-MDR-related drug 5-fluorouracil (5-FU) was able to induce MVP mRNA and protein expression. Treatment with 5-FU amplified the binding activity and interaction of the transcription factor Y-box binding protein-1 (YB-1) with the Y-box of the human MVP gene promoter in a time-dependent manner. 5-FU also induced reporter expressions driven by a panel of newly generated MVP promoter deletion mutants. Interestingly, stably YB-1 overexpressing cell clones showed enhanced binding of YB-1 to the Y-box motif, associated with enhanced basal as well as 5-FU-inducible MVP promoter-driven reporter expressions. Moreover, transduction of YB-1 cDNA led to increased expression of endogenous MVP protein. Under physiological conditions, we observed a strong coexpression of MVP and YB-1 in human colon carcinoma specimen. In summary, our data demonstrate a direct involvement of YB-1 in controlling basal and 5-FU-induced MVP promoter activity. Therefore, YB-1 is directly linked to MVP-mediated drug resistance.

DOI: 10.1038/sj.onc.1208386
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@article{Stein2005YB1FB, title={YB-1 facilitates basal and 5-fluorouracil-inducible expression of the human major vault protein (MVP) gene}, author={Ulrike Stein and Stephan Bergmann and George L . Scheffer and Rik J . Scheper and Hans-Dieter Royer and Peter M. Schlag and Wolfgang Walther}, journal={Oncogene}, year={2005}, volume={24}, pages={3606-3618} }