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

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.