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Modulation of drug resistance by artificial transcription factors.

Blancafort, Pilar and Tschan, Mario P and Bergquist, Sharon and Guthy, Daniel Alexander and Brachat, Arndt Holger and Sheeter, Dennis A and Torbett, Bruce E and Erdmann, Dirk and Barbas, Carlos F (2008) Modulation of drug resistance by artificial transcription factors. Molecular Cancer Therapeutics, 7 (3). pp. 688-697. ISSN 1535-7163

Abstract

The efficiency of chemotherapeutic treatments in cancer patients is often impaired by the acquisition of drug resistance. Cancer cells develop drug resistance through dysregulation of one or more genes or cellular pathways. To isolate efficient regulators of drug resistance in tumor cells, we have adopted a genome-wide scanning approach based on the screening of large libraries of artificial transcription factors (ATFs) made of three and six randomly assembled zinc finger domains. Zinc finger libraries were linked to a VP64 activation domain and delivered into a paclitaxel-sensitive tumor cell line. Following drug treatment, several ATFs were isolated that promoted drug resistance. One of these ATFs, 3ZF-1-VP, promoted paclitaxel resistance in cell lines having mutated or inactivated p53, such as MDA-MB-435 and Kaposi's sarcoma cell lines. 3ZF-1-VP also induced strong resistance to etoposide, vincristine, and cisplatinum. Linkage of a repression domain to the selected ATF resulted in enhanced sensitivity to multiple drugs, particularly vincristine, cisplatinum, and 5-fluorouracil. Small interfering RNA-mediated inhibition of p53 revealed that 3ZF-1-VP activated both p53-dependent and p53-independent mechanisms to promote survival, whereas other ATF required intact p53. Real-time expression analysis and DNA microarrays showed that several ATFs up-regulated targets of p53, such as the cyclin-dependent kinase inhibitor p21(WAF1/CIP1), and genes participating in the p14(ARF)-MDM2-p53 tumor suppressor pathway, such as hDMP1. Thus, ATF can be used to map genes and pathways involved in drug resistance phenotypes and have potential as novel therapeutic agents to inhibit drug resistance.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution
Keywords: zinc fingers; artificial transcription factors; drug resistance; p53; gene expression profiles
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Date Deposited: 14 Dec 2009 13:52
Last Modified: 31 Jan 2013 01:05
URI: https://oak.novartis.com/id/eprint/836

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