1. ¹Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strae 10, 13092 Berlin, Germany
2. ²Free University Amsterdam, Department of Pathology, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands
3. ³Center of Advanced European Studies and Research (caesar), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany
4. ⁴Division of Surgery and Surgical Oncology, Charité, Humboldt-University, Campus Berlin-Buch, Robert Rössle Clinic, Lindenberger Weg 80, 13122 Berlin, Germany

Correspondence: U Stein, E-mail: ustein@mdc-berlin.de

⁵Current address: Memorial Sloan-Kettering Cancer Center, Department of Pathology, 1275 York Avenue, Box 110, New York, NY 10021, USA

Received 20 August 2004; Revised 15 October 2004; Accepted 18 November 2004; Published online 7 March 2005.

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.