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Departments of
*
Pathology and
Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; and
Department of Hematology, Erasmus University, Rotterdam, The Netherlands
P-glycoprotein (Pgp) and vaults are associated with multidrug
resistance in tumor cells, but their physiological functions are not
yet clear. Pgp, the prototypical transmembrane transporter molecule,
may also facilitate the migration of skin dendritic cells (DC).
Vaults—ribonucleoprotein cell organelles, frequently overexpressed in
Pgp-negative drug-resistant tumor cells—have also been associated with
intracellular transport processes. Given the pivotal role of DC in
dealing with exposure to potentially harmful substances, the present
study was set out to examine the expression of Pgp and vaults during
differentiation and maturation of DC. DC were obtained from different
sources, including blood-derived monocytes, CD34+
mononuclear cells, and chronic myeloid leukemia cells. Whereas flow
cytometric and immunocytochemical analyses showed slightly augmented
levels of Pgp, up-regulation of vault expression during DC culturing
was strong, readily confirmed by Western blotting, and independent of
the source of DC. In further exploring the functional significance of
vault expression, it was found that supplementing DC cultures with
polyclonal or mAbs against the major vault protein led to lower
viabilities of LPS- or TNF-
-matured monocytes-DC. Moreover,
expression of critical differentiation, maturation, and costimulatory
molecules, including CD1a and CD83, was reduced and their capacity to
induce Ag-specific T cell proliferative and IFN-
release responses
was impaired. These data point to a role for vaults in both DC survival
and functioning as APC.
This article has been cited by other articles:
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  M. Herlevsen, G. Oxford, C. R. Owens, M. Conaway, and D. Theodorescu Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes Mol. Cancer Ther., June 1, 2007; 6(6): 1804 - 1813. [Abstract] [Full Text] [PDF]
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 K. A. Suprenant, N. Bloom, J. Fang, and G. Lushington The major vault protein is related to the toxic anion resistance protein (TelA) family J. Exp. Biol., March 15, 2007; 210(6): 946 - 955. [Abstract] [Full Text] [PDF]
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 R. van de Ven, M. C. de Jong, A. W. Reurs, A. J. N. Schoonderwoerd, G. Jansen, J. H. Hooijberg, G. L. Scheffer, T. D. de Gruijl, and R. J. Scheper Dendritic Cells Require Multidrug Resistance Protein 1 (ABCC1) Transporter Activity for Differentiation J. Immunol., May 1, 2006; 176(9): 5191 - 5198. [Abstract] [Full Text] [PDF]
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 E. Steiner, K. Holzmann, C. Pirker, L. Elbling, M. Micksche, H. Sutterluty, and W. Berger The major vault protein is responsive to and interferes with interferon-{gamma}-mediated STAT1 signals J. Cell Sci., February 1, 2006; 119(3): 459 - 469. [Abstract] [Full Text] [PDF]
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 M. H. Mossink, A. van Zon, E. Franzel-Luiten, M. Schoester, V. A. Kickhoefer, G. L. Scheffer, R. J. Scheper, P. Sonneveld, and E. A. C. Wiemer Disruption of the Murine Major Vault Protein (MVP/LRP) Gene Does Not Induce Hypersensitivity to Cytostatics Cancer Res., December 15, 2002; 62(24): 7298 - 7304. [Abstract] [Full Text] [PDF]
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