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Journal of Biomolecular Screening, Vol. 9, No. 1, 44-51 (2004)
DOI: 10.1177/1087057103260115
© 2004 Society for Biomolecular Sciences

Cell Lines for Drug Discovery: Elevating Target-Protein Levels Using Engineered Transcription Factors

Pei-Qi Liu

Sangamo BioSciences, Inc., Point Richmond Technology Center, Richmond, CA

Magda F. Morton

Johnson & Johnson Pharmaceutical Research & Discovery L.L.C., San Diego, CA

Andreas Reik

Sangamo BioSciences, Inc., Point Richmond Technology Center, Richmond, CA

Ragan de la Rosa

Sangamo BioSciences, Inc., Point Richmond Technology Center, Richmond, CA

Matthew C. Mendel

Sangamo BioSciences, Inc., Point Richmond Technology Center, Richmond, CA

Xiao-Yong Li

Sangamo BioSciences, Inc., Point Richmond Technology Center, Richmond, CA

Casey C. Case

Sangamo BioSciences, Inc., Point Richmond Technology Center, Richmond, CA ccase{at}sangamo.com

Carl O. Pabo

Sangamo BioSciences, Inc., Point Richmond Technology Center, Richmond, CA

Veronica Moreno

Johnson & Johnson Pharmaceutical Research & Discovery L.L.C., San Diego, CA

Ashley Kempf

Johnson & Johnson Pharmaceutical Research & Discovery L.L.C., San Diego, CA

Jayashree Pyati

Johnson & Johnson Pharmaceutical Research & Discovery L.L.C., San Diego, CA

Nigel P. Shankley

Johnson & Johnson Pharmaceutical Research & Discovery L.L.C., San Diego, CA

Drug discovery requires high-quality, high-throughput bioassays for lead identification and optimization. These assays are usually based on immortalized cell lines, which express the selected drug target either naturally or as a consequence of transfection with the cDNA encoding the target. Natural untransfected cell lines often fail to achieve the levels of expression required to provide assays of sufficient quality with a high enough signal-to-noise ratio. Unfortunately, the use of cDNA is increasingly restricted, as the sequences for more and more genes become subject to patent restrictions. To overcome these limitations, the authors demonstrate that engineered transcription factors with Cys2-His2 zinc finger DNA-binding domains can be used to effectively activate an endogenous gene of interest without the use of isolated cDNA of the target gene. Using this approach, the authors have generated a cell line that provides a high-quality and pharmacologically validated G-protein-coupled receptor bioassay. In principle, this technology is applicable to any gene of pharmaceutical importance in any cell type. (Journal of Biomolecular Screening 2004:44-51)

Key Words: cell-based high-throughput screening • zinc finger proteins • G-protein-coupled receptor • cholecystokinin B receptor • calcium-flux assay


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P.-Q. Liu, S. Tan, M. C. Mendel, R. J. Murrills, B. M. Bhat, B. Schlag, R. Samuel, J. J. Matteo, R. de la Rosa, K. Howes, et al.
Isogenic Human Cell Lines for Drug Discovery: Regulation of Target Gene Expression by Engineered Zinc-Finger Protein Transcription Factors
J Biomol Screen, June 1, 2005; 10(4): 304 - 313.
[Abstract] [PDF]