Vaults: a ribonucleoprotein particle involved in drug resistance?

Abstract

Vaults are ribonucleoprotein particles found in the cytoplasm of eucaryotic cells. The 13 MDa particles are composed of multiple copies of three proteins: an M(r) 100 000 major vault protein (MVP) and two minor vault proteins of M(r) 193 000 (vault poly-(ADP-ribose) polymerase) and M(r) 240 000 (telomerase-associated protein 1), as well as small untranslated RNA molecules of approximately 100 bases. Although the existence of vaults was first reported in the mid-1980s no function has yet been attributed to this organelle. The notion that vaults might play a role in drug resistance was suggested by the molecular identification of the lung resistance-related (LRP) protein as the human MVP. MVP/LRP was found to be overexpressed in many chemoresistant cancer cell lines and primary tumor samples of different histogenetic origin. Several, but not all, clinico-pathological studies showed that MVP expression at diagnosis was an independent adverse prognostic factor for response to chemotherapy. The hollow barrel-shaped structure of the vault complex and its subcellular localization indicate a function in intracellular transport. It was therefore postulated that vaults contributed to drug resistance by transporting drugs away from their intracellular targets and/or the sequestration of drugs. Here, we review the current knowledge on the vault complex and critically discuss the evidence that links vaults to drug resistance.

The nuclear affairs of PTEN

“…PTEN binds to MVP, a protein hypothesized to be a general carrier molecule for nuclear-cytoplasmic transport (Mossink et al, 2003), in yeast two-hybrid screens (Yu et al, 2002). Further analysis confirmed that this interaction occurs in both 293T and HeLa cells and localized the binding sites to the C2 domain of PTEN and the EF-hand pair (a calcium-binding motif) of MVP.…”

Expression of Noncoding Vault RNA in Human Malignant Cells and Its Importance in Mitoxantrone Resistance

“…Multidrug-resistant cell lines have been shown to use these routes to gain resistance to various drugs. The expected role of vaults in MDR is supported by the following evidence: (a) vaults and their components are upregulated in cells treated with cytotoxic compounds (6), (b) vaults are involved in nucleocytoplasmic transport (2,17), and (c) compounds that interact with the vaults (17). Despite these findings, until recently (18), the vault components were not shown to interact directly with chemotherapeutic compounds.…”

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

“…YB-1 has also been shown to induce basal and 5-fluorouracil-induced expression of the major vault protein (MVP/LRP) gene, the promoter of which contains a Ybox (Stein et al, 2005). In human malignancies, vault proteins are involved in acquiring drug resistance (Mossink et al, 2003). Taken together, these findings suggest that nuclear localization of YB-1 might play a key role in the acquisition of global drug resistance through transcriptional activation of relevant genes and the repair of damaged DNA (Kuwano et al, 2004).…”