A very early induction of major vault protein accompanied by increased drug resistance in U-937 cells.

Abstract	U-937 human leukemia cells were selected for resistance to doxorubicin in the presence or absence of a specific drug modulator that inhibits the activity of P-glycoprotein (Pgp), encoded by the multidrug-resistance gene (MDR1). Parental cells expressed low basal levels of the multidrug-resistance-associated gene (MRP1) and major vault protein (MVP) mRNAs and no MDR1 mRNA. Two doxorubicin-resistant cell lines were selected. Both drug-resistant cell lines upregulated the MVP mRNA level 1.5-fold within 1 cell passage. The MVP mRNA level continued to increase over time as the doxorubicin selection pressure was increased. MVP protein levels generally paralleled the mRNA levels. The 2 high molecular weight vault protein mRNAs were always expressed at constitutive levels. Fully formed vault particles consisting of the MVP, the 2 high molecular weight proteins and the vault RNA assembled and accumulated to increased levels in drug-selected cells. MVP induction is therefore the rate-limiting step for vault particle formation in U-937 cells. By passage 25 and thereafter, the selected cells were resistant to doxorubicin, etoposide, mitoxantrone and 5-fluorouracil by a pathway that was independent of MDR1, MRP1, MRP2 and breast cancer resistance protein. In summary, U-937 doxorubicin-selected cells are programmed to rapidly upregulate MVP mRNA levels, to accumulate vault particles and to become multidrug resistant.
Authors	Yi Hu, Andrew G Stephen, Jin Cao, Lee R Tanzer, Christopher A Slapak, Steadman D Harrison, Viswanath Devanarayan, Anne H Dantzig, James J Starling, Leonard H Rome, Robert E Moore
Journal	International journal of cancer (Int J Cancer) Vol. 97 Issue 2 Pg. 149-56 (Jan 10 2002) ISSN: 0020-7136 [Print] United States
PMID	11774257 (Publication Type: Journal Article)
Copyright	Copyright 2002 Wiley-Liss, Inc.
Chemical References	ABCG2 protein, human ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-Binding Cassette Transporters Antibiotics, Antineoplastic Antineoplastic Agents MRP2 protein, S cerevisiae Mitochondrial Proteins Multidrug Resistance-Associated Proteins Neoplasm Proteins RNA, Messenger RNA, Neoplasm Ribosomal Proteins Saccharomyces cerevisiae Proteins Vault Ribonucleoprotein Particles major vault protein Doxorubicin multidrug resistance-associated protein 1
Topics	ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism) ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-Binding Cassette Transporters (genetics, metabolism) Antibiotics, Antineoplastic (pharmacology) Antineoplastic Agents (pharmacology) Cell Compartmentation Doxorubicin (pharmacology) Drug Resistance, Neoplasm Heat-Shock Response Hot Temperature Humans Mitochondrial Proteins Multidrug Resistance-Associated Proteins (genetics, metabolism) Neoplasm Proteins Precipitin Tests RNA, Messenger (metabolism) RNA, Neoplasm (metabolism) Reverse Transcriptase Polymerase Chain Reaction Ribosomal Proteins (genetics, metabolism) Saccharomyces cerevisiae Proteins U937 Cells (drug effects, metabolism) Up-Regulation Vault Ribonucleoprotein Particles (biosynthesis, genetics)

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