Journal
MOLECULAR CELL
Volume 12, Issue 6, Pages 1615-1624Publisher
CELL PRESS
DOI: 10.1016/S1097-2765(03)00491-X
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Funding
- NCI NIH HHS [CA39612] Funding Source: Medline
- NIGMS NIH HHS [GM68589] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R37CA039612, R01CA039612] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM068589] Funding Source: NIH RePORTER
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We have developed a general method of making conditional alleles that allows the rapid and reversible regulation of specific proteins. A mouse line was produced in which proteins encoded by the endogenous glycogen synthase kinase-3 beta (GSK-3beta) gene are fused to an 89 amino acid tag, FRB*. FRB* causes the destabilization of GSK-3beta, producing a severe loss-of-function allele. In the presence of C20-MaRap, a highly specific, nontoxic, cell-permeable small molecule, GSK-3betaFRB* binds to the ubiquitously expressed FKBP12 protein. This interaction stabilizes GSK-3betaFRB* and restores both protein levels and activity. C20-MaRap-mediated stabilization is rapidly reversed by the addition of an FKBP12 binding competitor molecule. This technology may be applied to a wide range of FRB*-tagged mouse genes while retaining their native transcriptional control. Inducible stabilization could be valuable for many developmental and physiological studies and for drug target validation.
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