Chemical genetics: exploring the role of the proteasome in cell biology using natural products and other small molecule proteasome inhibitors.

Abstract

In the era of systemic proteomics, temporal and spatial control of protein functions has become very important in the investigation of complex biological processes in vivo. While traditional genetic manipulations have provided a powerful tool to study protein function, these applications are limited by the possibility that some mutant phenotypes may be due to compensatory responses that occur during development. In addition, gene knockout models that are embryonic lethal are not amenable to study disease processes that occur in the adult animal. Moreover, the inhibition of the target gene’s function is often irreversible, and thus, the desired biological effect(s) cannot be readily regulated. This makes it difficult to dissect the precise role of proteins in complex signaling pathways. Recently, small interfering RNA (siRNAa) has been widely used to modulate protein function at the RNA level.1 However, this technique offers limited temporal control of gene expression. Difficulties with the nonspecificity and delivery of siRNAs have also been major concerns. The use of small-molecule probes is one way to complement these genetic approaches. Most biologically active small molecules including natural products exert their activities via inhibition of specific biological processes. In comparison to the classical genetic approach, this small molecule approach easily affords more temporal and spatial control of targeted biological events. A small molecule approach, being complementary to the classical genetic approach, is thus fittingly dubbed “chemical genetics”.2 Although many areas of biology have benefited from the chemical genetics approach, few have been more broadly and significantly impacted than the biology and biochemistry of the proteasome.