The Experts below are selected from a list of 777 Experts worldwide ranked by ideXlab platform
Rik J Scheper - One of the best experts on this subject based on the ideXlab platform.
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yb 1 facilitates basal and 5 fluorouracil inducible expression of the human Major Vault Protein mvp gene
Oncogene, 2005Co-Authors: Ulrike Stein, Hansdieter Royer, Stephan Bergmann, Peter M. Schlag, George L. Scheffer, Rik J Scheper, Wolfgang WaltherAbstract: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.
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Efflux Kinetics and Intracellular Distribution of Daunorubicin Are Not Affected by Major Vault Protein/Lung Resistance-Related Protein (Vault) Expression
Cancer Research, 2004Co-Authors: Arend Van Zon, Marieke H. Mossink, Pieter Sonneveld, Rik J Scheper, Erik A.c. WiemerAbstract:Vaults may contribute to multidrug resistance by transporting drugs away from their subcellular targets. To study the involvement of Vaults in the extrusion of anthracyclines from the nucleus, we investigated the handling of daunorubicin by drug-sensitive and drug-resistant non-small lung cancer cells, including a green fluorescent Protein (GFP)-tagged Major Vault Protein (MVP)-overexpressing transfectant (SW1573/MVP-GFP). Cells were exposed to 1 microm daunorubicin for 60 min, after which the cells were allowed to efflux the accumulated drug. No significant differences in daunorubicin efflux kinetics were observed between the sensitive SW1573 and SW1573/MVP-GFP transfectant, whereas the drug-resistant SW1573/2R120 cells clearly demonstrated an increased efflux rate. It was noted that the redistribution of daunorubicin from the nucleus into distinct vesicular structures in the cytoplasm was not accompanied by changes in the intracellular localization of Vaults. Similar experiments were performed using mouse embryonic fibroblasts derived from wild-type and MVP knockout mice, which were previously shown to be devoid of Vault particles. Both cell lines showed comparable drug efflux rates, and the intracellular distribution of daunorubicin in time was identical. Reintroduction of a human MVP tagged with GFP in the MVP(-/-) cells results in the formation of Vault particles but did not give rise an altered daunorubicin handling compared with MVP(-/-) cells expressing GFP. Our results indicate that Vaults are not directly involved in the sequestration of anthracyclines in vesicles nor in their efflux from the nucleus.
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efflux kinetics and intracellular distribution of daunorubicin are not affected by Major Vault Protein lung resistance related Protein Vault expression
Cancer Research, 2004Co-Authors: Arend Van Zon, Marieke H. Mossink, Pieter Sonneveld, Rik J Scheper, Erik A.c. WiemerAbstract:Vaults may contribute to multidrug resistance by transporting drugs away from their subcellular targets. To study the involvement of Vaults in the extrusion of anthracyclines from the nucleus, we investigated the handling of daunorubicin by drug-sensitive and drug-resistant non-small lung cancer cells, including a green fluorescent Protein (GFP)-tagged Major Vault Protein (MVP)-overexpressing transfectant (SW1573/MVP-GFP). Cells were exposed to 1 microm daunorubicin for 60 min, after which the cells were allowed to efflux the accumulated drug. No significant differences in daunorubicin efflux kinetics were observed between the sensitive SW1573 and SW1573/MVP-GFP transfectant, whereas the drug-resistant SW1573/2R120 cells clearly demonstrated an increased efflux rate. It was noted that the redistribution of daunorubicin from the nucleus into distinct vesicular structures in the cytoplasm was not accompanied by changes in the intracellular localization of Vaults. Similar experiments were performed using mouse embryonic fibroblasts derived from wild-type and MVP knockout mice, which were previously shown to be devoid of Vault particles. Both cell lines showed comparable drug efflux rates, and the intracellular distribution of daunorubicin in time was identical. Reintroduction of a human MVP tagged with GFP in the MVP(-/-) cells results in the formation of Vault particles but did not give rise an altered daunorubicin handling compared with MVP(-/-) cells expressing GFP. Our results indicate that Vaults are not directly involved in the sequestration of anthracyclines in vesicles nor in their efflux from the nucleus.
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expression and cellular distribution of multidrug resistance related Proteins in the hippocampus of patients with mesial temporal lobe epilepsy
Epilepsia, 2004Co-Authors: Eleonora Aronica, Marja Ramkema, Filiz Ozbasgerceker, S. Redeker, Edwin A Van Vliet, Jan A. Gorter, George L. Scheffer, Paul Van Der Valk, Rik J Scheper, Johannes C BaayenAbstract:Summary: Purpose: This study investigated the cellular distribution of different multidrug resistance (MDR)-related Proteins such as P-glycoProtein (P-gp), the multidrug resistance–associated Proteins (MRP) 1 and 2, and the Major Vault Protein (MVP) in normal and sclerotic hippocampus of patients with medically refractory mesial temporal lobe epilepsy (MTLE). Methods: Single- and double-label immunocytochemistry was used on brain sections of control hippocampus and of hippocampus of refractory MTLE patients. Results: In TLE cases with hippocampal sclerosis (HS), all four MDR Proteins examined that had low or no expression in control tissue were upregulated, albeit with different cellular distribution patterns. P-gp immunoreactivity (IR) was observed in astrocytes in regions with diffuse reactive gliosis. In 75% of HS cases, strong P-gp IR was detected in blood vessels, with prominent endothelial labeling. Reactive astrocytes displayed low MRP1 IR. However, glial MRP1 expression was noted in glial endfoot processes around blood vessels. Neuronal MRP1 expression was observed in hypertrophic hilar neurons and in a few residual neurons of the CA1 region. Hippocampal MRP2 expression was observed in the large Majority of HS cases in blood vessels. Hypertrophic hilar neurons and blood vessels within the sclerotic hippocampus expressed Major Vault Protein (MVP). Conclusions: These findings indicate that MDR Proteins are upregulated in concert in the hippocampus of patients with refractory MTLE, supporting their role in the mechanisms underlying drug resistance. The specific cell-distribution patterns within the sclerotic hippocampus suggest different cellular functions, not necessarily linked only to clinical drug resistance.
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Expression of multidrug resistance Proteins P-glycoProtein, multidrug resistance Protein 1, breast cancer resistance Protein and lung resistance related Protein in locally advanced bladder cancer treated with neoadjuvant chemotherapy: biological and clinical implications.
The Journal of Urology, 2003Co-Authors: Julio E. Diestra, George L. Scheffer, Rik J Scheper, E. Condom, Xavier Garcia Del Muro, J. Pérez, Amado J. Zurita, José Muñoz-seguí, Francisco Vigués, Gabriel CapelláAbstract:ABSTRACTPurpose: Resistance to chemotherapy is a Major obstacle to overcome in the conservative treatment of patients with locally advanced bladder cancer (LABC). We investigated the predictive value of the response to neoadjuvant chemotherapy (NACT) and prognosis of the expression of multidrug resistance (MDR) related Proteins, P-glycoProtein (P-gp), multidrug resistance Protein 1 (MRP1), breast cancer resistance Protein (BCRP) and lung resistance related Protein/Major Vault Protein (LRP/MVP) in LABC.Materials and Methods: Using immunohistochemistry we studied the expression of MDR Proteins in tumors from 83 patients with LABC treated with NACT using a bladder sparing approach. Expression was related to the response to NACT, bladder preservation and prognosis.Results: P-gp, MRP1, BCRP and LRP/MVP were expressed at high levels in 53%, 59%, 28% and 70% of cases, respectively. P-gp expression correlated with shorter progression-free survival (p = 0.04) but not with overall survival. Surprisingly MRP1 expres...
Erik A.c. Wiemer - One of the best experts on this subject based on the ideXlab platform.
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Research Article Major Vault Protein, in Concert with Constitutively Photomorphogenic 1, Negatively Regulates c-Jun–Mediated Activator Protein 1 Transcription in Mammalian Cells
2014Co-Authors: Xishu Chen, Erik A.c. Wiemer, Jian Wang, Ning Wei, Xing Wang DengAbstract:Constitutively photomorphogenic 1 (COP1), a RING finger ubiquitin ligase with substrates including c-Jun and p53, was recently found to be overexpressed in a number of breast and ovarian tumor samples. In addition to its E3 activity, COP1 was also shown to be able to inhibit activator Protein 1 (AP-1) transcription. Through an affinity purification method, we have identified Major Vault Protein (MVP) as a novel interacting partner for COP1 in mammalian cells. MVP, also known as lung resistance Protein, is the main component of a ribonucleoProtein organelle called Vault, and has been implicated in multiple drug resistance in many cancer cell lines and primary tumor samples. The interaction between COP1 and MVP is detectable at the endogenous level and occurs mostly in the cytoplasm. Similar to COP1, MVP inhibits c-Jun accumulation and AP-1 transcription activity. MVP knockout or knockdown cells contain elevated amount of c-Jun and increased AP-1 transcription activity. UV irradiation enhances MVP tyrosine phosphorylation, causes dissociation of COP1 from MVP, and alleviates the inhibitory activity of MVP on AP-1 transcription. Taken together, we propose that MVP, most likely through its interaction with COP1, suppresses c-Jun–mediated AP-1 transcription under unstressed conditions, thereby preventing cells from undergoing stress response. (Cancer Res 2005; 65(13): 5835-40
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Recruitment of the Major Vault Protein by InlK: a Listeria monocytogenes strategy to avoid autophagy.
PLoS Pathogens, 2011Co-Authors: Laurent Dortet, Erik A.c. Wiemer, Serge Mostowy, Ascel Samba Louaka, Edith Gouin, Marie-anne Nahori, Olivier Dussurget, Pascale CossartAbstract:L. monocytogenes is a facultative intracellular bacterium responsible for listeriosis. It is able to invade, survive and replicate in phagocytic and non-phagocytic cells. The infectious process at the cellular level has been extensively studied and many virulence factors have been identified. Yet, the role of InlK, a member of the internalin family specific to L. monocytogenes, remains unknown. Here, we first show using deletion analysis and in vivo infection, that InlK is a bona fide virulence factor, poorly expressed in vitro and well expressed in vivo, and that it is anchored to the bacterial surface by sortase A. We then demonstrate by a yeast two hybrid screen using InlK as a bait, validated by pulldown experiments and immunofluorescence analysis that intracytosolic bacteria via an interaction with the Protein InlK interact with the Major Vault Protein (MVP), the main component of cytoplasmic ribonucleoproteic particules named Vaults. Although Vaults have been implicated in several cellular processes, their role has remained elusive. Our analysis demonstrates that MVP recruitment disguises intracytosolic bacteria from autophagic recognition, leading to an increased survival rate of InlK over-expressing bacteria compared to InlK− bacteria. Together these results reveal that MVP is hijacked by L. monocytogenes in order to counteract the autophagy process, a finding that could have Major implications in deciphering the cellular role of Vault particles.
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Recruitment of the Major Vault Protein by Inlk: a Listeria monocytogenes strategy to avoid autophagy
2011Co-Authors: Laurent Dortet, Erik A.c. Wiemer, Serge Mostowy, Ascel Samba Louaka, Edith Gouin, Olivier Dussurget, Pascale CossartAbstract:L. monocytogenes is a facultative intracellular bacterium responsible for listeriosis. It is able to invade, survive and replicate in phagocytic and non-phagocytic cells. The infectious process at the cellular level has been extensively studied and many virulence factors have been identified. Yet, the role of InlK, a member of the internalin family specific to L. monocytogenes, remains unknown. Here, we first show using deletion analysis and in vivo infection, that InlK is a bona fide virulence factor, poorly expressed in vitro and well expressed in vivo, and that it is anchored to the bacterial surface by sortase A. We then demonstrate by a yeast two hybrid screen using InlK as a bait, validated by pulldown experiments and immunofluorescence analysis that intracytosolic bacteria via an interaction with the Protein InlK interact with the Major Vault Protein (MVP), the main component of cytoplasmic ribonucleoproteic particules named Vaults. Although Vaults have been implicated in several cellular processes, their role has remained elusive. Our analysis demonstrates that MVP recruitment disguises intracytosolic bacteria from autophagic recognition, leading to an increased survival rate of InlK over-expressing bacteria compared to InlK2 bacteria. Together these results reveal that MVP is hijacked by L. monocytogenes in order to counterac
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Efflux Kinetics and Intracellular Distribution of Daunorubicin Are Not Affected by Major Vault Protein/Lung Resistance-Related Protein (Vault) Expression
Cancer Research, 2004Co-Authors: Arend Van Zon, Marieke H. Mossink, Pieter Sonneveld, Rik J Scheper, Erik A.c. WiemerAbstract:Vaults may contribute to multidrug resistance by transporting drugs away from their subcellular targets. To study the involvement of Vaults in the extrusion of anthracyclines from the nucleus, we investigated the handling of daunorubicin by drug-sensitive and drug-resistant non-small lung cancer cells, including a green fluorescent Protein (GFP)-tagged Major Vault Protein (MVP)-overexpressing transfectant (SW1573/MVP-GFP). Cells were exposed to 1 microm daunorubicin for 60 min, after which the cells were allowed to efflux the accumulated drug. No significant differences in daunorubicin efflux kinetics were observed between the sensitive SW1573 and SW1573/MVP-GFP transfectant, whereas the drug-resistant SW1573/2R120 cells clearly demonstrated an increased efflux rate. It was noted that the redistribution of daunorubicin from the nucleus into distinct vesicular structures in the cytoplasm was not accompanied by changes in the intracellular localization of Vaults. Similar experiments were performed using mouse embryonic fibroblasts derived from wild-type and MVP knockout mice, which were previously shown to be devoid of Vault particles. Both cell lines showed comparable drug efflux rates, and the intracellular distribution of daunorubicin in time was identical. Reintroduction of a human MVP tagged with GFP in the MVP(-/-) cells results in the formation of Vault particles but did not give rise an altered daunorubicin handling compared with MVP(-/-) cells expressing GFP. Our results indicate that Vaults are not directly involved in the sequestration of anthracyclines in vesicles nor in their efflux from the nucleus.
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efflux kinetics and intracellular distribution of daunorubicin are not affected by Major Vault Protein lung resistance related Protein Vault expression
Cancer Research, 2004Co-Authors: Arend Van Zon, Marieke H. Mossink, Pieter Sonneveld, Rik J Scheper, Erik A.c. WiemerAbstract:Vaults may contribute to multidrug resistance by transporting drugs away from their subcellular targets. To study the involvement of Vaults in the extrusion of anthracyclines from the nucleus, we investigated the handling of daunorubicin by drug-sensitive and drug-resistant non-small lung cancer cells, including a green fluorescent Protein (GFP)-tagged Major Vault Protein (MVP)-overexpressing transfectant (SW1573/MVP-GFP). Cells were exposed to 1 microm daunorubicin for 60 min, after which the cells were allowed to efflux the accumulated drug. No significant differences in daunorubicin efflux kinetics were observed between the sensitive SW1573 and SW1573/MVP-GFP transfectant, whereas the drug-resistant SW1573/2R120 cells clearly demonstrated an increased efflux rate. It was noted that the redistribution of daunorubicin from the nucleus into distinct vesicular structures in the cytoplasm was not accompanied by changes in the intracellular localization of Vaults. Similar experiments were performed using mouse embryonic fibroblasts derived from wild-type and MVP knockout mice, which were previously shown to be devoid of Vault particles. Both cell lines showed comparable drug efflux rates, and the intracellular distribution of daunorubicin in time was identical. Reintroduction of a human MVP tagged with GFP in the MVP(-/-) cells results in the formation of Vault particles but did not give rise an altered daunorubicin handling compared with MVP(-/-) cells expressing GFP. Our results indicate that Vaults are not directly involved in the sequestration of anthracyclines in vesicles nor in their efflux from the nucleus.
George L. Scheffer - One of the best experts on this subject based on the ideXlab platform.
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yb 1 facilitates basal and 5 fluorouracil inducible expression of the human Major Vault Protein mvp gene
Oncogene, 2005Co-Authors: Ulrike Stein, Hansdieter Royer, Stephan Bergmann, Peter M. Schlag, George L. Scheffer, Rik J Scheper, Wolfgang WaltherAbstract: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.
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expression and cellular distribution of multidrug resistance related Proteins in the hippocampus of patients with mesial temporal lobe epilepsy
Epilepsia, 2004Co-Authors: Eleonora Aronica, Marja Ramkema, Filiz Ozbasgerceker, S. Redeker, Edwin A Van Vliet, Jan A. Gorter, George L. Scheffer, Paul Van Der Valk, Rik J Scheper, Johannes C BaayenAbstract:Summary: Purpose: This study investigated the cellular distribution of different multidrug resistance (MDR)-related Proteins such as P-glycoProtein (P-gp), the multidrug resistance–associated Proteins (MRP) 1 and 2, and the Major Vault Protein (MVP) in normal and sclerotic hippocampus of patients with medically refractory mesial temporal lobe epilepsy (MTLE). Methods: Single- and double-label immunocytochemistry was used on brain sections of control hippocampus and of hippocampus of refractory MTLE patients. Results: In TLE cases with hippocampal sclerosis (HS), all four MDR Proteins examined that had low or no expression in control tissue were upregulated, albeit with different cellular distribution patterns. P-gp immunoreactivity (IR) was observed in astrocytes in regions with diffuse reactive gliosis. In 75% of HS cases, strong P-gp IR was detected in blood vessels, with prominent endothelial labeling. Reactive astrocytes displayed low MRP1 IR. However, glial MRP1 expression was noted in glial endfoot processes around blood vessels. Neuronal MRP1 expression was observed in hypertrophic hilar neurons and in a few residual neurons of the CA1 region. Hippocampal MRP2 expression was observed in the large Majority of HS cases in blood vessels. Hypertrophic hilar neurons and blood vessels within the sclerotic hippocampus expressed Major Vault Protein (MVP). Conclusions: These findings indicate that MDR Proteins are upregulated in concert in the hippocampus of patients with refractory MTLE, supporting their role in the mechanisms underlying drug resistance. The specific cell-distribution patterns within the sclerotic hippocampus suggest different cellular functions, not necessarily linked only to clinical drug resistance.
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Expression of multidrug resistance Proteins P-glycoProtein, multidrug resistance Protein 1, breast cancer resistance Protein and lung resistance related Protein in locally advanced bladder cancer treated with neoadjuvant chemotherapy: biological and clinical implications.
The Journal of Urology, 2003Co-Authors: Julio E. Diestra, George L. Scheffer, Rik J Scheper, E. Condom, Xavier Garcia Del Muro, J. Pérez, Amado J. Zurita, José Muñoz-seguí, Francisco Vigués, Gabriel CapelláAbstract:ABSTRACTPurpose: Resistance to chemotherapy is a Major obstacle to overcome in the conservative treatment of patients with locally advanced bladder cancer (LABC). We investigated the predictive value of the response to neoadjuvant chemotherapy (NACT) and prognosis of the expression of multidrug resistance (MDR) related Proteins, P-glycoProtein (P-gp), multidrug resistance Protein 1 (MRP1), breast cancer resistance Protein (BCRP) and lung resistance related Protein/Major Vault Protein (LRP/MVP) in LABC.Materials and Methods: Using immunohistochemistry we studied the expression of MDR Proteins in tumors from 83 patients with LABC treated with NACT using a bladder sparing approach. Expression was related to the response to NACT, bladder preservation and prognosis.Results: P-gp, MRP1, BCRP and LRP/MVP were expressed at high levels in 53%, 59%, 28% and 70% of cases, respectively. P-gp expression correlated with shorter progression-free survival (p = 0.04) but not with overall survival. Surprisingly MRP1 expres...
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disruption of the murine Major Vault Protein mvp lrp gene does not induce hypersensitivity to cytostatics
Cancer Research, 2002Co-Authors: Marieke H. Mossink, Arend Van Zon, Erna Franzelluiten, Valerie A. Kickhoefer, George L. Scheffer, Pieter Sonneveld, Rik J Scheper, Erik A.c. WiemerAbstract:Vaults are ribonucleoProtein particles with a distinct structure and a high degree of conservation between species. Although no function has been assigned to the complex yet, there is some evidence for a role of Vaults in multidrug resistance. To confirm a direct relation between Vaults and multidrug resistance, and to investigate other possible functions of Vaults, we have generated a Major Vault Protein (MVP/lung resistance-related Protein) knockout mouse model. The MVP / mice are viable, healthy, and show no obvious abnormalities. We investigated the sensitivity of MVP / embryonic stem cells and bone marrow cells derived from the MVP-deficient mice to various cytostatic agents with different mechanisms of action. Neither the MVP / embryonic stem cells nor the MVP / bone marrow cells showed an increased sensitivity to any of the drugs examined, as compared with wild-type cells. Furthermore, the activities of the ABC-transporters P-glycoProtein, multidrug resistanceassociated Protein and breast cancer resistance Protein were unaltered on MVP deletion in these cells. In addition, MVP wild-type and deficient mice were treated with the anthracycline doxorubicin. Both groups of mice responded similarly to the doxorubicin treatment. Our results suggest that MVP/Vaults are not directly involved in the resistance to cytostatic agents.
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lung resistance related Protein Major Vault Protein and Vaults in multidrug resistant cancer
Current Opinion in Oncology, 2000Co-Authors: George L. Scheffer, Erik A.c. Wiemer, Miguel A Izquierdo, A B Schroeijers, Rik J ScheperAbstract:Tumor cells that are insensitive to anticancer drugs frequently have a multidrug-resistant (MDR) phenotype. Proteins that can be involved in this phenomenon are transport-associated Proteins such as P-glycoProtein, multidrug-resistance Protein 1, breast cancer resistance Protein, and lung resistance-related Protein (LRP). LRP was identified as the Major Vault Protein (MVP), the main component of multimeric Vault particles. With the recent identification of the two minor Vault Proteins as telomerase-associated Protein (TEP1) and Vault-poly (ADP-ribose) polymerase (VPARP), and with high-resolution three-dimensional imaging, the composition of Vaults is almost unraveled. Although the first direct evidence for a causal relationship between LRP/MVP expression and drug resistance has been obtained, many functional aspects of Vaults in normal physiology and in MDR still need to be clarified. The current clinical data on LRP/MVP detection indicate that LRP/MVP expression can be of high clinical value to predict the response to chemotherapy of several tumor types.
Pieter Sonneveld - One of the best experts on this subject based on the ideXlab platform.
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CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age
Annals of Hematology, 2007Co-Authors: Marry M. Heuvel-eibrink, Gert J Ossenkoppele, Bob Lowenberg, Bronno Holt, Alan K. Burnett, Wolfgang U. Knauf, Martin F. Fey, Gregor E. G. Verhoef, Edo Vellenga, Pieter SonneveldAbstract:Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) Proteins P-glycoProtein, encoded by the MDR1 / ABCB1 gene, multidrug resistant-related Protein (MRP/ABCC1), the lung resistance-related Protein (LRP), or Major Vault Protein (MVP), and the breast cancer resistance Protein (BCRP/ABCG2). The clinical value of MDR1 , MRP1 , LRP / MVP , and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients ≥60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p
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Efflux Kinetics and Intracellular Distribution of Daunorubicin Are Not Affected by Major Vault Protein/Lung Resistance-Related Protein (Vault) Expression
Cancer Research, 2004Co-Authors: Arend Van Zon, Marieke H. Mossink, Pieter Sonneveld, Rik J Scheper, Erik A.c. WiemerAbstract:Vaults may contribute to multidrug resistance by transporting drugs away from their subcellular targets. To study the involvement of Vaults in the extrusion of anthracyclines from the nucleus, we investigated the handling of daunorubicin by drug-sensitive and drug-resistant non-small lung cancer cells, including a green fluorescent Protein (GFP)-tagged Major Vault Protein (MVP)-overexpressing transfectant (SW1573/MVP-GFP). Cells were exposed to 1 microm daunorubicin for 60 min, after which the cells were allowed to efflux the accumulated drug. No significant differences in daunorubicin efflux kinetics were observed between the sensitive SW1573 and SW1573/MVP-GFP transfectant, whereas the drug-resistant SW1573/2R120 cells clearly demonstrated an increased efflux rate. It was noted that the redistribution of daunorubicin from the nucleus into distinct vesicular structures in the cytoplasm was not accompanied by changes in the intracellular localization of Vaults. Similar experiments were performed using mouse embryonic fibroblasts derived from wild-type and MVP knockout mice, which were previously shown to be devoid of Vault particles. Both cell lines showed comparable drug efflux rates, and the intracellular distribution of daunorubicin in time was identical. Reintroduction of a human MVP tagged with GFP in the MVP(-/-) cells results in the formation of Vault particles but did not give rise an altered daunorubicin handling compared with MVP(-/-) cells expressing GFP. Our results indicate that Vaults are not directly involved in the sequestration of anthracyclines in vesicles nor in their efflux from the nucleus.
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efflux kinetics and intracellular distribution of daunorubicin are not affected by Major Vault Protein lung resistance related Protein Vault expression
Cancer Research, 2004Co-Authors: Arend Van Zon, Marieke H. Mossink, Pieter Sonneveld, Rik J Scheper, Erik A.c. WiemerAbstract:Vaults may contribute to multidrug resistance by transporting drugs away from their subcellular targets. To study the involvement of Vaults in the extrusion of anthracyclines from the nucleus, we investigated the handling of daunorubicin by drug-sensitive and drug-resistant non-small lung cancer cells, including a green fluorescent Protein (GFP)-tagged Major Vault Protein (MVP)-overexpressing transfectant (SW1573/MVP-GFP). Cells were exposed to 1 microm daunorubicin for 60 min, after which the cells were allowed to efflux the accumulated drug. No significant differences in daunorubicin efflux kinetics were observed between the sensitive SW1573 and SW1573/MVP-GFP transfectant, whereas the drug-resistant SW1573/2R120 cells clearly demonstrated an increased efflux rate. It was noted that the redistribution of daunorubicin from the nucleus into distinct vesicular structures in the cytoplasm was not accompanied by changes in the intracellular localization of Vaults. Similar experiments were performed using mouse embryonic fibroblasts derived from wild-type and MVP knockout mice, which were previously shown to be devoid of Vault particles. Both cell lines showed comparable drug efflux rates, and the intracellular distribution of daunorubicin in time was identical. Reintroduction of a human MVP tagged with GFP in the MVP(-/-) cells results in the formation of Vault particles but did not give rise an altered daunorubicin handling compared with MVP(-/-) cells expressing GFP. Our results indicate that Vaults are not directly involved in the sequestration of anthracyclines in vesicles nor in their efflux from the nucleus.
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disruption of the murine Major Vault Protein mvp lrp gene does not induce hypersensitivity to cytostatics
Cancer Research, 2002Co-Authors: Marieke H. Mossink, Arend Van Zon, Erna Franzelluiten, Valerie A. Kickhoefer, George L. Scheffer, Pieter Sonneveld, Rik J Scheper, Erik A.c. WiemerAbstract:Vaults are ribonucleoProtein particles with a distinct structure and a high degree of conservation between species. Although no function has been assigned to the complex yet, there is some evidence for a role of Vaults in multidrug resistance. To confirm a direct relation between Vaults and multidrug resistance, and to investigate other possible functions of Vaults, we have generated a Major Vault Protein (MVP/lung resistance-related Protein) knockout mouse model. The MVP / mice are viable, healthy, and show no obvious abnormalities. We investigated the sensitivity of MVP / embryonic stem cells and bone marrow cells derived from the MVP-deficient mice to various cytostatic agents with different mechanisms of action. Neither the MVP / embryonic stem cells nor the MVP / bone marrow cells showed an increased sensitivity to any of the drugs examined, as compared with wild-type cells. Furthermore, the activities of the ABC-transporters P-glycoProtein, multidrug resistanceassociated Protein and breast cancer resistance Protein were unaltered on MVP deletion in these cells. In addition, MVP wild-type and deficient mice were treated with the anthracycline doxorubicin. Both groups of mice responded similarly to the doxorubicin treatment. Our results suggest that MVP/Vaults are not directly involved in the resistance to cytostatic agents.
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do p glycoProtein and Major Vault Protein mvp lrp expression correlate with in vitro daunorubicin resistance in acute myeloid leukemia
Leukemia, 1999Co-Authors: H J Broxterman, Pieter Sonneveld, R Pieters, J Lankelma, C A Eekman, A H Loonen, Gert J Ossenkoppele, Bob Lowenberg, H M PinedoAbstract:Do P-glycoProtein and Major Vault Protein (MVP/LRP) expression correlate with in vitro daunorubicin resistance in acute myeloid leukemia?
Miguel A Izquierdo - One of the best experts on this subject based on the ideXlab platform.
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lung resistance related Protein Major Vault Protein and Vaults in multidrug resistant cancer
Current Opinion in Oncology, 2000Co-Authors: George L. Scheffer, Erik A.c. Wiemer, Miguel A Izquierdo, A B Schroeijers, Rik J ScheperAbstract:Tumor cells that are insensitive to anticancer drugs frequently have a multidrug-resistant (MDR) phenotype. Proteins that can be involved in this phenomenon are transport-associated Proteins such as P-glycoProtein, multidrug-resistance Protein 1, breast cancer resistance Protein, and lung resistance-related Protein (LRP). LRP was identified as the Major Vault Protein (MVP), the main component of multimeric Vault particles. With the recent identification of the two minor Vault Proteins as telomerase-associated Protein (TEP1) and Vault-poly (ADP-ribose) polymerase (VPARP), and with high-resolution three-dimensional imaging, the composition of Vaults is almost unraveled. Although the first direct evidence for a causal relationship between LRP/MVP expression and drug resistance has been obtained, many functional aspects of Vaults in normal physiology and in MDR still need to be clarified. The current clinical data on LRP/MVP detection indicate that LRP/MVP expression can be of high clinical value to predict the response to chemotherapy of several tumor types.
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lung resistance related Protein Major Vault Protein and Vaults in multidrug resistant cancer
Current Opinion in Oncology, 2000Co-Authors: George L. Scheffer, Erik A.c. Wiemer, Miguel A Izquierdo, A B Schroeijers, Rik J ScheperAbstract:Tumor cells that are insensitive to anticancer drugs frequently have a multidrug-resistant (MDR) phenotype. Proteins that can be involved in this phenomenon are transport-associated Proteins such as P-glycoProtein, multidrug-resistance Protein 1, breast cancer resistance Protein, and lung resistance
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Vault related resistance to anticancer drugs determined by the expression of the Major Vault Protein lrp
Cytotechnology, 1998Co-Authors: Miguel A Izquierdo, George L. Scheffer, A B Schroeijers, Mariska C De Jong, Rik J ScheperAbstract:In this review we analyze the data supporting the notion that Vault-related MDR, as reflected by LRP/MVP overexpression, represents a marker of drug resistance in vitro and in the clinic. Vaults, besides playing a fundamental biological role, may be involved in a novel mechanism of MDR.
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broad distribution of the multidrug resistance related Vault lung resistance Protein in normal human tissues and tumors
American Journal of Pathology, 1996Co-Authors: Miguel A Izquierdo, Henricus J Broxterman, G Giaccone, M J Flens, G L Scheffer, C J L M Meijer, Van Der Valk P, R J ScheperAbstract:Multidrug resistance (MDR) to anticancer drugs is a Major cause of treatment failure in cancer. The lung resistance Protein LRP is a newly described Protein related to MDR in several in vitro models. LRP has been shown to be a strong predictor of poor response to chemotherapy and prognosis in acute myeloid leukemia and in ovarian carcinoma patients. Recently, based on a 57% and 88% amino acid identity with Major Vault Proteins from Dictyostelium discoideum and Rattus norvegicus, respectively, we identified LRP as the human Major Vault Protein, the main component of highly conserved cellular organelles named Vaults. We have studied the immunohistochemical expression of LRP in freshly frozen normal human tissues and 174 cancer specimens of 28 tumor types. LRP was broadly distributed in normal and malignant cells, but distinct patterns of expression were noticed. High LRP expression was seen in bronchus, digestive tract, renal proximal tubules, keratinocytes, macrophages, and adrenal cortex whereas varying ing levels were observed in other organs. LRP was detected in all tumor types examined, but its frequency varied, fairly reflecting the chemosensitivity of different cancers. For example, low rates of LRP positivity were seen in testicular cancer, neuroblastoma, and acute myeloid leukemia; intermediate in ovarian cancer; and high in colon, renal, and pancreatic carcinomas. The wide occurrence of LRP in normal and transformed cells in humans, its similar distribution to that of Vaults in other species, as well as the high level of conservation among eukaryotic cells of both the amino acid sequence of the Major Vault Protein and the composition and structure of Vaults, suggest that Vault function is important to eukaryotic cells.
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relationship of lrp human Major Vault Protein to in vitro and clinical resistance to anticancer drugs
Cytotechnology, 1996Co-Authors: Miguel A Izquierdo, George L. Scheffer, M J Flens, Robert H Shoemaker, Leonard H Rome, Rik J ScheperAbstract:Multidrug resistance (MDR) has been related to two members of the ABC-superfamily of transporters, P-glycoProtein (Pgp) and Multidrug Resistance-associated Protein (MRP). We have described a 110 kD Protein termed the Lung Resistance-related Protein (LRP) that is overexpressed in several non-Pgp MDR cell lines of different histogenetic origin. Reversal of MDR parallels a decrease in LRP expression. In a panel of 61 cancer cell lines which have not been subjected to laboratory drug selection, LRP was a superior predictor forin vitro resistance to MDR-related drugs when compared to Pgp and MRP, and LRP's predictive value extended to MDR unrelated drugs, such as platinum compounds. LRP is widely distributed in clinical cancer specimens, but the frequency of LRP expression inversely correlates with the known chemosensitivity of different tumour types. Furthermore, LRP expression at diagnosis has been shown to be a strong and independent prognostic factor for response to chemotherapy and outcome in acute myeloid leukemia and ovarian carcinoma (platinum-based treatment) patients. Recently, LRP has been identified as the human Major Protein. Vaults are novel cellular organelles broadly distributed and highly conserved among diverse eukaryotic cells, suggesting that they play a role in fundamental cell processes. Vaults localise to nuclear pore complexes and may be the central plug of the nuclear pore complexes. Vaults structure and localisation support a transport function for this particle which could involve a variety of substrates. Vaults may therefore play a role in drug resistance by regulating the nucleocytoplasmic transport of drugs.
