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WTH3, which Encodes a Small G Protein, Is Differentially Regulated in Multidrug-Resistant and Sensitive MCF7 Cells

¹ Department of Biochemistry and Cell Biology, State University of New York at Stony Brook, Stony Brook, New York; ² North Shore-Long Island Jewish Research Institute, Manhasset, New York; and ³ Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York

Requests for reprints: Haopeng Xu, Department of Biochemistry and Cell Biology, State University of New York at Stony Brook, R474 Life Science Building, Stony Brook, NY 11794-5215. Phone: 631-632-8566; Fax: 631-632-8575; E-mail: hduffy{at}notes.cc.sunysb.edu.

The WTH3 gene's biological characteristics and relationship to multidrug resistance (MDR) were investigated further. Results showed that WTH3 was mainly located in the cytosol and capable of binding to GTP. In addition, WTH3's promoter function was significantly attenuated in MDR (MFC7/AdrR) relative to non-MDR (MCF7/WT) cells. Advanced analyses indicated that two mechanisms could be involved in WTH3's down-regulation: DNA methylation and trans-element modulations. It was found that the 5' end portion of a CpG island in WTH3's promoter was hypermethylated in MCF7/AdrR but not MCF7/WT cells, which could have a negative effect on the WTH3 promoter. This idea was supported by the observation that a 45-bp sequence (DMR45) in this differentially methylated region positively influenced promoter activity. We also discovered that different nuclear proteins in MCF7/AdrR and MCF7/WT cells bound to methylated or nonmethylated DMR45. Moreover, a sequence containing a unique repeat that was also a positive cis-element for the promoter was attached by different transcription factors depending on whether they were prepared from MCF7/AdrR or MCF7/WT cells. These molecular changes, apparently induced by drug treatment, resulted in WTH3's down regulation in MDR cells. Therefore, present studies support previous observations that WTH3, as a negative regulator, participates in MDR development in MCF7/AdrR cells.

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