Analysis of MVP and VPARP promoters indicates a role for chromatin remodeling in the regulation of MVP.
Multi-drug-resistant cancer cells frequently express elevated levels of ribonucleoprotein complexes termed vaults. The increased expression of vault proteins and their mRNAs has led to the suggestion that vaults may play a direct role in preventing drug toxicity. To further understand vault component up-regulation, the three proteins that comprise the vault, the major vault protein (MVP), vault poly(ADP-ribose) polymerase (VPARP), and telomerase-associated protein-1 (TEP1), were examined with respect to gene amplification and drug-induced chromatin remodeling. Gene amplification was not responsible for increased vault component levels in multi-drug-resistant cancer cell lines. The TATA-less murine MVP and human VPARP promoters were identified and functionally characterized. There was no significant activation of either the MVP or VPARP promoters in drug-resistant cell lines in comparison to their parental, drug-sensitive counterparts. Treatment of various cell lines with sodium butyrate, an inhibitor of histone deacetylase (HDAC), led to an increase in vault component protein levels. Furthermore, treatment with trichostatin A (TSA), a more specific inhibitor of HDAC, caused an increase in MVP protein, mRNA, and promoter activity. These results suggest that up-regulation of MVP in multi-drug resistance (MDR) may involve chromatin remodeling.
Emre
Nil
N
The Department of Biological Chemistry and the Jonsson Comprehensive Cancer Center, The David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1737, USA.
Raval-Fernandes
Sujna
S
Kickhoefer
Valerie A
VA
Rome
Leonard H
LH
D000818:Animals; D001483:Base Sequence; D002087:Butyrates / Q000494:pharmacology; D002352:Carrier Proteins; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics*; D000099187:Major Vault Protein
D002087:Butyrates; D002352:Carrier Proteins; D011065:Poly(ADP-ribose) Polymerases; D016601:RNA-Binding Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C104342:TEP1 protein, human; C498415:Tep1 protein, mouse; C449359:vault poly(ADP-ribose) polymerase