The major vault protein is responsive to and interferes with interferon-γ-mediated STAT1 signals

Steiner, Elisabeth; Holzmann, Klaus; Pirker, Christine; Elbling, Leonilla; Micksche, M.; Sutterlüty, Hedwig; Berger, Walter

doi:10.1242/jcs.02773

Cited by 80 publications

(95 citation statements)

References 37 publications

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“…Several recent studies have suggested that MVP is involved in cell survival following stress or damage, 34,35 but apparently plays no role in development as MVP knockout mice exhibit no discernible developmental abnormalities. 35 We have recently shown that increased levels of Bcl-2 contribute to apoptotic resistance in senescent HDFs.…”

Section: Discussionmentioning

confidence: 99%

On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis

Ryu

et al. 2008

Cell Death Differ

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Major vault protein (MVP), the main component of vault complex, is overexpressed in many multidrug-resistant cancer cell lines, suggesting a possible role for MVP in cell signaling and survival. In this study, we have found that MVP is markedly increased in senescent human diploid fibroblasts (HDFs) as well as in aged organs. We examined whether MVP expression might be affected by apoptotic stress in an aging-dependent manner. We treated young and senescent HDFs with apoptosis-inducing agents such as H 2 O 2 , staurosporine and thapsigargin, and monitored MVP expression. We found that MVP expression is markedly reduced in young HDFs but not in senescent HDFs, in response to apoptotic stresses. Downregulation of MVP increased the sensitivity of senescent HDFs to apoptosis. Also, the level of antiapoptotic B-cell lymphoma protein-2 (Bcl-2) was significantly reduced and the accumulation of c-Jun increased in MVP knocked-down senescent HDFs. Moreover, treatment of MVP knocked-down senescent HDFs with SP600125, a specific c-Jun NH (2) Vaults are large ribonucleoprotein particles found in a great portion of eukaryotic cells. The vault particle is a multimeric structure composed of three proteins -the major vault protein (MVP), two minor vault proteins, vault poly (ADP-ribose) polymerase (VPARP) and telomerase-associated protein-1 (TP-1), and four small untranslated vault RNAs (vRNAs). 1 MVP is the main component of the vault complex accounting for 75% of the total particle mass. 2 The vault particle has been so named because it has a barrel-shaped structure, reminiscent of the vaulted ceilings in cathedrals. 3 The interaction of MVP by its coiled coil domain is involved in the formation of the basic vault complex. 4 MVP expression is upregulated in cancers such as melanoma, 5 colon cancer 6 and gliomas 7 during acquisition of multidrug resistance 8,9 and during differentiation of dendritic cells. 10 MVP expression has also been shown to be induced by histone deacetylase inhibitors such as sodium butyrate, 11 phorbol 12-myristate 13-acetate (PMA) and cytarabine 12 as well as by cytotoxic drugs. 12-14 MVP/vaults have been proposed to be important in intracellular transport, 15-17 innate immunity 18 and virus infection. 19 Several studies demonstrated that MVP is important in cell signaling [20][21][22] and in cell survival. 10,20,23 For example, serumdeprived MVP-deficient mouse embryonic fibroblasts (MEFs) exhibit significantly increased cell death when compared with wild-type MEFs. 20 Therefore, the role of MVP as a scaffolding protein for signaling proteins, especially for cell survival, has received more attention than as a transport vehicle. However, the exact role of MVP in cell survival is not well understood. In this study, we found that apoptotic resistance of senescent human diploid fibroblasts (HDFs) correlates with the increased content of MVP in the senescent cells. This is the first report implicating MVP in apoptosis resistance of senescent HDFs. ResultsIncreased expression of MVP in aged cells and organs...

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Section: Discussionmentioning

confidence: 99%

On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis

Ryu

et al. 2008

Cell Death Differ

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“…MVP/vaults have been associated with multidrug resistance (21)(22)(23), nuclear-cytoplasmic transport (24), innate immunity (25), autophagy (26), and signal transduction pathways (27)(28)(29)(30)(31); however, the precise function of MVP/ vault remains enigmatic. Our previous work indicating MVPinduced type I IFN production upon hepatitis C virus infection uncovers a new role of MVP in modulating innate immunity during viral infection (32).…”

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confidence: 99%

Inducible Major Vault Protein Plays a Pivotal Role in Double-Stranded RNA– or Virus-Induced Proinflammatory Response

Peng

Shi

Xia

et al. 2016

The Journal of Immunology

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Pathogen invasion triggers robust antiviral cytokine production via different transcription factor signaling pathways. We have previously demonstrated that major vault protein (MVP) induces type I IFN production during viral infection; however, little is known about the role of MVP in proinflammatory responses. In this study, we found in vitro that expression of MVP, IL-6, and IL-8 was inducible upon dsRNA stimulation or viral infection. Moreover, MVP was essential for the induction of IL-6 and IL-8, as impaired expression of IL-6 and IL-8 in MVP-deficient human PBMCs, human lung epithelial cells (A549), and THP-1 monocytes, as well as in murine splenocytes, peritoneal macrophages, and PBMCs from MVP-knockout (MVP−/−) mice, was observed. Upon investigation of the underlying mechanisms, we demonstrated that MVP acted in synergy with AP-1 (c-Fos) and CCAAT/enhancer binding protein (C/EBP)β–liver-enriched transcriptional activating protein to activate the IL6 and IL8 promoters. Introduction of mutations into the AP-1 and C/EBPβ binding sites on the IL6 and IL8 promoters resulted in the loss of synergistic activation with MVP. Furthermore, we found that MVP interacted with both c-Fos and C/EBPβ. The interactions promoted nuclear translocation and recruitment of these transcription factors to IL6 and IL8 promoter regions. In the MVP−/− mouse model, significantly decreased expression of early antiviral cytokines resulted in higher viral titer in the lung, higher mortality, and heavier lung damage after infection with lethal influenza A virus. Taken together, our findings help to delineate a novel role of MVP in host proinflammatory response.

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“…Similarly, Siva et al (51) demonstrated that the upregulation of MVP is not sufficient to confer an MDR phenotype. In addition, recent studies have correlated MVP with several signaling pathways (52)(53)(54)(55)(56) and immune responses (57)(58)(59)(60), which imply that the function of MVP may be more complex than expected. Thirdly, the inability to find an association between variants of the MVP gene and platinum resistance or survival in the present study may be due to the limited number of patients enrolled in the study, since the number of patients in the subgroup was below the statistical threshold.…”

Section: Discussionmentioning

confidence: 99%

Association of single nucleotide polymorphisms in the MVP gene with platinum resistance and survival in patients with epithelial ovarian cancer

Wang

2016

Oncology Letters

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Abstract. The human major vault protein (MVP) has been linked to the development of multidrug resistance in cancer cells, and overexpression of MVP has been observed in ovarian cancer tissues. The aim of the present study was to investigate the association between single nucleotide polymorphisms (SNPs) in the MVP gene and the tumor response to platinum-based chemotherapy and survival of patients affected by epithelial ovarian cancer (EOC), in addition to confirm whether tetra-primer amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR) is an accurate genotyping method. For this purpose, two polymorphisms in the MVP gene, namely reference SNP (rs)1057451 and rs4788186, were selected from the data obtained by the International haplotype map (HapMap) Project regarding Chinese Han population, and were evaluated by tetra-primer ARMS-PCR. Upon validation by DNA sequencing, the association of these polymorphisms with platinum resistance, progression-free survival (PFS) and overall survival (OS) in patients with EOC was assessed. The results of tetra-primer ARMS-PCR were in agreement with those derived from DNA sequencing. No significant differences were observed between platinum-sensitive and platinum-resistant cohorts in terms of allele and genotype distribution of these two polymorphisms in the MVP gene, which were not associated with PFS or OS. However, a trend toward prolonged PFS was observed in patients carrying the heterozygous AG allele at the rs4788186 locus. These results suggest that rs1057451 and rs4788186 variants in the MVP gene are not associated with favorable therapeutic response to platinum or longer survival in Chinese Han patients affected by EOC. In addition, the data of the present study confirm that tetra-primer ARMS-PCR is a trustworthy and economical genotyping method.

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The major vault protein is responsive to and interferes with interferon-γ-mediated STAT1 signals

Abstract: These data further substantiate that the vault particle functions as a general interaction platform for cellular signaling cascades.

Cited by 80 publications

References 37 publications

On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis

On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis

Inducible Major Vault Protein Plays a Pivotal Role in Double-Stranded RNA– or Virus-Induced Proinflammatory Response

Association of single nucleotide polymorphisms in the MVP gene with platinum resistance and survival in patients with epithelial ovarian cancer

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