Emre Nil, Raval-Fernandes Sujna, Kickhoefer Valerie A, Rome Leonard H
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.
Biochim Biophys Acta. 2004 Apr 16;1678(1):33-46. doi: 10.1016/j.bbaexp.2004.01.005.
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.
多药耐药癌细胞经常表达称为穹窿体的核糖核蛋白复合物的水平升高。穹窿体蛋白及其mRNA表达的增加表明，穹窿体可能在预防药物毒性方面发挥直接作用。为了进一步了解穹窿体成分的上调情况，对构成穹窿体的三种蛋白质，即主要穹窿体蛋白（MVP）、穹窿体聚（ADP-核糖）聚合酶（VPARP）和端粒酶相关蛋白-1（TEP1），进行了基因扩增和药物诱导的染色质重塑方面的研究。基因扩增并非多药耐药癌细胞系中穹窿体成分水平增加的原因。鉴定并对无TATA盒的小鼠MVP和人VPARP启动子进行了功能表征。与它们的亲代药物敏感细胞系相比，耐药细胞系中MVP或VPARP启动子均未出现明显激活。用组蛋白脱乙酰酶（HDAC）抑制剂丁酸钠处理各种细胞系，导致穹窿体成分蛋白水平增加。此外，用更特异的HDAC抑制剂曲古抑菌素A（TSA）处理，导致MVP蛋白、mRNA和启动子活性增加。这些结果表明，多药耐药（MDR）中MVP的上调可能涉及染色质重塑。
