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Chem Biol. 2012 Mar 23;19(3):391-8. doi: 10.1016/j.chembiol.2011.12.022.

Targeted chemical-genetic regulation of protein stability in vivo.

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Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.


Loss- and gain-of-function transgenic models are powerful tools for understanding gene function in vivo but are limited in their ability to determine relative protein requirements. To determine cell-specific, temporal, or dose requirements of complex pathways, new methodology is needed. This is particularly important for deconstructing metabolic pathways that are highly interdependent and cross-regulated. We have combined mouse conditional transgenics and synthetic posttranslational protein stabilization to produce a broadly applicable strategy to regulate protein and pathway function in a cell-autonomous manner in vivo. Here, we show how a targeted chemical-genetic strategy can be used to alter fatty acid metabolism in a reombination and small-molecule-dependent manner in live behaving transgenic mice. This provides a practical, specific, and reversible means of manipulating metabolic pathways in adult mice to provide biological insight.

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