Harnessing the ubiquitination machinery to target the degradation of specific cellular proteins

The functional characterization of a specific gene, or its protein product, often relies on assessing the consequences of its elimination, usually acc omplished by gene knockout, ribozyme, antisense, or RNA-mediated interferen ce (RNAi) technologies. The selective degradation of cellular proteins is m ediated primarily by the ubiquitin-proteasome pathway. Manipulation of the ubiquitin-dependent proteolytic machinery to eliminate specific gene produc ts at the protein level has been previously attempted with some success in vitro; however, the in vivo efficacy of this approach has not yet been achi eved. Here we report successful engineering of the substrate receptor of a major ubiquitin-proteolytic machinery to direct the degradation of otherwis e stable cellular proteins both in yeast and in mammalian cells.