Alternative titles; symbols
HGNC Approved Gene Symbol: MVP
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38) : 16:29,820,394-29,848,039 (from NCBI)
Vaults are hollow intracellular organelles with dimensions of about 57 by 32 nm and a nuclear mass of about 13 MD, 3 times the size of a ribosome. They are composed of a small RNA (VTRNA1-1; 612695), the 100-kD major vault protein (MVP), and minor vault proteins of 193 kD (PARP4; 607519) and 240 kD (TEP1; 601686). MVP accounts for over 70% of the particle mass (Izquierdo et al., 1996; Kickhoefer et al., 1999).
Multidrug-resistant (MDR) cancer cells frequently overexpress the 110-kD lung resistance-related protein (LRP). Overexpression of LRP often predicts a poor response to chemotherapy. By screening a multidrug-resistant non-P-glycoprotein (see ABCB1; 171050) fibrosarcoma cell line with an LRP-specific monoclonal antibody, Scheffer et al. (1995) isolated a cDNA encoding LRP. The deduced 896-amino acid LRP protein shares 88% amino acid identity with the rat major vault protein (Mvp). RNase protection assays showed that LRP expression was enhanced 4- to 8-fold in non-P-glycoprotein MDR cell lines.
Using immunohistochemical analysis, Izquierdo et al. (1996) found that LRP was widely expressed in normal and tumor tissues and showed a characteristic cytoplasmic granular pattern. High LRP expression was detected in the epithelial lining of bronchioles and upper and lower digestive tract, renal proximal tubules, epidermal keratinocytes and melanocytes, macrophages, and adrenal cortex. Lower and variable expression of LRP was detected in other tissues. LRP was expressed in all tumor types tested, and its level of expression fairly reflected the chemosensitivity of the tumors, with lower expression in highly chemosensitive tumors. Immunoprecipitated LRP had an apparent molecular mass of 110 kD by SDS-PAGE.
By EST database analysis, Holzmann et al. (2001) identified a long MVP splice variant, L-MVP, that contains a 41-bp stretch in the 5-prime region that is intronic in the shorter S-MVP splice variant. This 41-bp stretch introduces an upstream ORF encoding a deduced 18-amino acid peptide. RT-PCR detected ubiquitous expression of both variants, and S-MVP was always the major variant.
Van Zon et al. (2002) identified a central calcium-binding EF-hand motif and a C-terminal coiled-coil domain in MVP.
Using confocal immunocytochemistry with anti-MVP antibody, Slesina et al. (2005) found a dense distribution of vault particles in the cytoplasm of human U373 astroglioma cell line. A punctate staining pattern was also detected in the nucleus. Cryoimmunoelectron microscopy revealed clusters of immunogold particles at nuclear pores and in the nucleoplasm, suggesting that nuclear MVP was also associated with vaults. Quantification of fluorescent MVP in the cytosol and nucleus of U373 cells revealed about 5% of MVP in the nucleus.
By proteomic analysis, Vuorinen et al. (2017) identified MVP as a KPNA7 (614107) cargo protein in human pancreatic cancer cell lines. Fractionation analysis showed that ZNF414 was almost exclusively nuclear, and immunofluorescence assays confirmed nuclear localization.
Kickhoefer et al. (1998) found that expression of MVP and VTRNA1-1 and assembly of vaults increased up to 15-fold in several drug-resistant cell lines compared with the parental cell lines. They hypothesized that the absolute vault level in cell lines may dictate the extent of drug resistance.
Abbondanza et al. (1998) found that MVP coprecipitated with estrogen receptor (ER, or ESR1; 133430) from nuclear extracts of MCF-7 human breast cancer cells and that ER associated with intact vaults. Mutation analysis showed that a central region of ER containing nuclear localization signals was involved in the interaction. A limited amount of ER molecules in the nuclear extract appeared to be associated with MVP. Physiologic concentrations of estradiol increased the amount of MVP present in MCF-7 nuclear extracts and coimmunoprecipitated with ER. The hormone-dependent interaction of vaults with ER was reproduced in vitro. Antibodies to progesterone receptor (PGR; 607311) and glucocorticoid receptor (GCCR; 138040) also coimmunoprecipitated MVP, but more weakly.
By yeast 2-hybrid analysis and by in vitro binding assays with recombinant proteins, Kickhoefer et al. (1999) confirmed direct interaction between MVP and PARP4, which they called VPARP. The C-terminal domain was the smallest sequence of PARP4 that could bind MVP. The PARP-like catalytic domain, when expressed as a recombinant protein in E. coli, showed ADP-ribosylase activity. Vault particles purified from rat liver and incubated with radiolabeled NAD showed prominent ADP-ribosylation of Mvp and some automodification of Parp4.
Holzmann et al. (2001) showed that in vitro translation of L-MVP was low relative to translation of S-MVP. Mutation of the start codon of the upstream ORF in the L-MVP transcript reversed the suppression of MVP translation, suggesting that translation of the upstream ORF controls expression of the larger protein.
Using yeast 2- and 3-hybrid analysis and mutation analysis, van Zon et al. (2002) found that MVP molecules interacted with each other via their coiled-coil domains. MVP also bound calcium, likely via its EF-hand motif. The N-terminal half of MVP bound a C-terminal domain of VPARP, but TEP1 did not appear to interact with either MVP or VPARP.
Using a yeast 2-hybrid screen, Yu et al. (2002) showed that MPV interacted with PTEN (601728), a protein phosphatase that can function as a tumor suppressor. Endogenous PTEN associated with vault particles isolated from HeLa cells. Coimmunoprecipitation analysis confirmed the interaction between PTEN and MVP. Deletion analysis mapped the interacting regions to the C2 domain of PTEN and the EF-hand motifs of MVP. The interaction was independent of tyrosine phosphorylation, but required calcium, consistent with a calcium-induced conformational change in the MVP EF-hand motifs.
Using human airway epithelial cells, Kowalski et al. (2007) showed that MVP accumulated rapidly into lipid rafts during Pseudomonas aeruginosa infection, and this accumulation was markedly reduced in cells from cystic fibrosis (219700) patients expressing the delF508 mutation (602421.0001) in CFTR (602421). Immunofluorescence microscopy and coimmunoprecipitation experiments demonstrated colocalization of bacteria, CFTR, and MVP, without direct physical association. The outer core oligosaccharide of P. aeruginosa bound CFTR and was required for recruitment of MVP to lipid rafts. Small interfering RNA-mediated knockdown of MVP decreased recruitment of MVP to lipid rafts following P. aeruginosa infection without affecting NFKB (see 164011) activation, IL8 (146930) secretion, or apoptosis induction, suggesting a key role for MVP in bacterial uptake.
Vuorinen et al. (2017) found that silencing of KPNA7 increased cytoplasmic MVP levels and decreased nuclear MVP levels, confirming that KPNA7 transported MVP to the nucleus. Silencing of MVP in pancreatic cancer cells resulted in a decrease in cell number, suggesting that MVP is a regulator of pancreatic cancer cell growth.
Lange et al. (2000) determined that the MVP gene contains 15 exons. They found that the promoter region has an inverted CCAAT box but no TATA box. They identified several putative promoter binding sites including an SP1 (189901)-binding site located close to a p53 (191170)-binding motif. An alternative 3-prime splice site of intron 1 results in a splicing variant within the 5-prime untranslated region of MVP mRNA.
By FISH, Scheffer et al. (1995) mapped the LRP gene to chromosome 16p13.1-p11.2, in the same chromosomal region as the MDR-associated genes MRP (ABCC1; 158343) and PRKCB1 (176970). The authors noted that acute myeloid leukemia patients with a deletion of an MRP gene, resulting from a chromosome 16 inversion, often have a favorable outcome.
Kowalski et al. (2007) found that Mvp -/- mice infected with P. aeruginosa internalized fewer bacteria in lung epithelial cells than wildtype mice, resulting in increased bacterial burden in the lung. Mvp -/- mice also had increased mortality after P. aeruginosa infection. Kowalski et al. (2007) concluded that MVP contributes to resistance against P. aeruginosa lung infection.
Abbondanza, C., Rossi, V., Roscigno, A., Gallo, L., Belsito, A., Piluso, G., Medici, N., Nigro, V., Molinari, A. M., Moncharmont, B., Puca, G. A. Interaction of vault particles with estrogen receptor in the MCF-7 breast cancer cell. J. Cell Biol. 141: 1301-1310, 1998. [PubMed: 9628887] [Full Text: https://doi.org/10.1083/jcb.141.6.1301]
Holzmann, K., Ambrosch, I., Elbling, L., Micksche, M., Berger, W. A small upstream open reading frame causes inhibition of human major vault protein expression from a ubiquitous mRNA splice variant. FEBS Lett. 494: 99-104, 2001. [PubMed: 11297743] [Full Text: https://doi.org/10.1016/s0014-5793(01)02318-3]
Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Giaccone, G., Broxterman, H. J., Meijer, C. J. L. M., van der Valk, P., Scheper, R. J. Broad distribution of the multidrug resistance-related vault lung resistance protein in normal human tissues and tumors. Am. J. Path. 148: 877-887, 1996. [PubMed: 8774142]
Kickhoefer, V. A., Rajavel, K. S., Scheffer, G. L., Dalton, W. S., Scheper, R. J., Rome, L. H. Vaults are up-regulated in multidrug-resistant cancer cell lines. J. Biol. Chem. 273: 8971-8974, 1998. [PubMed: 9535882] [Full Text: https://doi.org/10.1074/jbc.273.15.8971]
Kickhoefer, V. A., Siva, A. C., Kedersha, N. L., Inman, E. M., Ruland, C., Streuli, M., Rome, L. H. The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase. J. Cell Biol. 146: 917-928, 1999. [PubMed: 10477748] [Full Text: https://doi.org/10.1083/jcb.146.5.917]
Kickhoefer, V. A., Stephen, A. G., Harrington, L., Robinson, M. O., Rome, L. H. Vaults and telomerase share a common subunit, TEP1. J. Biol. Chem. 274: 32712-32717, 1999. [PubMed: 10551828] [Full Text: https://doi.org/10.1074/jbc.274.46.32712]
Kowalski, M. P., Dubouix-Bourandy, A., Bajmoczi, M., Golan, D. E., Zaidi, T., Coutinho-Sledge, Y. S., Gygi, M. P., Gygi, S. P., Wiemer, E. A. C., Pier, G. B. Host resistance to lung infection mediated by major vault protein in epithelial cells. Science 317: 130-132, 2007. [PubMed: 17615361] [Full Text: https://doi.org/10.1126/science.1142311]
Lange, C., Walther, W., Schwabe, H., Stein, U. Cloning and initial analysis of the human multidrug resistance-related MVP/LRP gene promoter. Biochem. Biophys. Res. Commun. 278: 125-133, 2000. [PubMed: 11071864] [Full Text: https://doi.org/10.1006/bbrc.2000.3782]
Scheffer, G. L., Wijngaard, P. L. J., Flens, M. J., Izquierdo, M. A., Slovak, M. L., Pinedo, H. M., Meijer, C. J. L. M., Clevers, H. C., Scheper, R. J. The drug resistance-related protein LRP is the human major vault protein. Nature Med. 1: 578-582, 1995. [PubMed: 7585126] [Full Text: https://doi.org/10.1038/nm0695-578]
Slesina, M., Inman, E. M., Rome, L. H., Volknandt, W. Nuclear localization of the major vault protein in U373 cells. Cell Tissue Res. 321: 97-104, 2005. [PubMed: 15902504] [Full Text: https://doi.org/10.1007/s00441-005-1086-8]
van Zon, A., Mossink, M. H., Schoester, M., Scheffer, G. L., Scheper, R. J., Sonneveld, P., Wiemer, E. A. C. Structural domains of vault proteins: a role for the coiled coil domain in vault assembly. Biochem. Biophys. Res. Commun. 291: 535-541, 2002. [PubMed: 11855821] [Full Text: https://doi.org/10.1006/bbrc.2002.6472]
Vuorinen, E. M., Rajala, N. K., Rauhala, H. E., Nurminen, A. T., Hytonen, V. P., Kallioniemi, A. Search for KPNA7 cargo proteins in human cells reveals MVP and ZNF414 as novel regulators of cancer cell growth. Biochim. Biophys. Acta Molec. Basis Dis. 1863: 211-219, 2017. [PubMed: 27664836] [Full Text: https://doi.org/10.1016/j.bbadis.2016.09.015]
Yu, Z., Fotouhi-Ardakani, N., Wu, L., Maoui, M., Wang, S., Banville, D., Shen, S.-H. PTEN associates with the vault particles in HeLa cells. J. Biol. Chem. 277: 40247-40252, 2002. [PubMed: 12177006] [Full Text: https://doi.org/10.1074/jbc.M207608200]