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Papers In Press, published online ahead of print February 9, 2004
Pharmacology and Toxicology, IUPUI, Indiamapolis, IN 46202
Corresponding Author: asafa{at}iupui.edu
RNA helicase A (RHA) is a member of the DEAD/H family of RNA helicases and unwinds duplex RNA and DNA. Recent studies showed that RHA regulates the activity of gene promoters. However, little information is available about the in vivo relevance of RHA in the regulation of natural genes. We previously characterized a nuclear protein (MEF1) that binds to the proximal promoter of the multidrug resistant (MDR1) gene and upregulats the promoter activity. In the present study, we isolated and identified RHA as a component of the MEF1 complex by using DNA-affinity chromatography and mass spectrometry. The antibody against RHA specifically disrupted the complex formation in EMSA, confirming the identity of RHA. Western blotting showed that RHA in drug resistant cells had a higher molecular weight than that in sensitive cells. Similar results were obtained when Flag-tagged RHA was overexpressed in these cells. This size difference probably reflects posttranslational modification(s) of RHA in resistant cells. Chromatin immunoprecipitation revealed that RHA occupies the MDR1 promoter in vivo. Overexpression of RHA enhanced expression of the MDR1 promoter/reporter construct and endogenous P-glycoprotein (P-gp), the MDR1 gene product, and increased drug resistance of resistant cells but not the drug sensitive counterpart. Introduction of short interfering RNA (siRNA) targeting the RHA gene sequence selectively knocked-down RHA expression and concomitantly reduced P-gp level. Thus, our study demonstrates, for the first time, the involvement of RHA in upregulation of the MDR1 gene. Interactions of RHA with other protein factors in the MEF1 complex bound to the promoter element may contribute to P-gp overexpression and MDR phenotype in drug resistant cancer cells.
J. Biol. Chem, 10.1074/jbc.M311057200
Submitted on October 8, 2003
Revised on February 3, 2004
Accepted on February 9, 2004
RNA helicase A in the MEF1 transcription factor complex upregulates the MDR1 gene in multidrug resistant cancer cells
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