The goal of this proposal is to determine the function of vaults. Vaults are the largest cytoplasmic ribonucleoprotein particle known. Their considerable abundance and striking evolutionary conservation among eukaryotes argue for an important general cellular function. The existence of this particle was first reported 10 years ago and this grant has been the primary source of support for vault studies since it was first funded in 1987. In addition to identifying structure, composition, tissue and cellular distribution of this particle, past studies have also produced valuable reagents that will be essential for elucidating vault function. The hypothesis that vaults function in nucleocytoplasmic transport has received recent attention from investigators working on the mechanism of resistance of cancer cells to chemotherapy. Multidrug resistance (MDR), the major cause of chemotherapy failure, is a process whereby cancer cells treated with one drug develop resistance to a wide variety of unrelated agents to which the cells have not been exposed. It was recently reported that the human major vault protein (MVP) is overexpressed in a class of MDR cell lines whose drug resistance cannot be explained by the expression of known drug efflux pumps (p-glycoprotein and MDR-associated protein). Furthermore, MVP showed the greatest individual value as a marker for in vitro resistance of human cancer cell lines to a broad variety of drugs and MVP expression appears to have a high predictive value for resistance to chemotherapy in acute myeloid leukemia and ovarian carcinoma. Molecular, cell biological and immunological tools will be applied to test the hypothesis that vault expression is responsible for MDR. Vault induction in cancer cells will be examined and it will be determined whether vaults act directly to protect these cells from drug toxicity. Protein expression and antisense technology will be used to interfere with vault structure and function in MDR cells. If these manipulations lead to increased drug sensitivity they will establish a causative relationship between vault expression and MDR.
| Slesina, Marco; Inman, Elisabeth M; Moore, Ann E et al. (2006) Movement of vault particles visualized by GFP-tagged major vault protein. Cell Tissue Res 324:403-10 |
| Emre, Nil; Raval-Fernandes, Sujna; Kickhoefer, Valerie A et al. (2004) Analysis of MVP and VPARP promoters indicates a role for chromatin remodeling in the regulation of MVP. Biochim Biophys Acta 1678:33-46 |
| Kickhoefer, Valerie A; Poderycki, Michael J; Chan, Edward K L et al. (2002) The La RNA-binding protein interacts with the vault RNA and is a vault-associated protein. J Biol Chem 277:41282-6 |
| Siva, A C; Raval-Fernandes, S; Stephen, A G et al. (2001) Up-regulation of vaults may be necessary but not sufficient for multidrug resistance. Int J Cancer 92:195-202 |
| Kickhoefer, V A; Liu, Y; Kong, L B et al. (2001) The Telomerase/vault-associated protein TEP1 is required for vault RNA stability and its association with the vault particle. J Cell Biol 152:157-64 |
| Stephen, A G; Raval-Fernandes, S; Huynh, T et al. (2001) Assembly of vault-like particles in insect cells expressing only the major vault protein. J Biol Chem 276:23217-20 |
| Schroeijers, A B; Siva, A C; Scheffer, G L et al. (2000) The Mr 193,000 vault protein is up-regulated in multidrug-resistant cancer cell lines. Cancer Res 60:1104-10 |
| Kong, L B; Siva, A C; Kickhoefer, V A et al. (2000) RNA location and modeling of a WD40 repeat domain within the vault. RNA 6:890-900 |
| Kickhoefer, V A; Siva, A C; Kedersha, N L et al. (1999) The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase. J Cell Biol 146:917-28 |
| Kickhoefer, V A; Stephen, A G; Harrington, L et al. (1999) Vaults and telomerase share a common subunit, TEP1. J Biol Chem 274:32712-7 |
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