Proteasome-mediated degradation of transcriptional activators correlates with activation domain potency in vivo

We show that the intracellular concentration of transcriptional activator p roteins is regulated by the proteasome-mediated protein degradation pathway . The rate of degradation of activators by proteasomes correlates with acti vation domain potency in vivo. Mutations either in the activation domain re sidues involved in target protein interaction or in the DNA-binding domain residues essential for DNA binding abolish the transcriptional activation f unction in vivo and render the activator resistant to degradation by protea somes. Finally, using a rapamycin-regulated gene expression system, we show that recruiting activation domains to DNA-bound receptor proteins greatly enhanced the rate of degradation of reconstituted activators. These observa tions suggest that in mammalian cells efficient recruitment of activator-ta rget protein complexes to the promoter means that they are subjected to rap id degradation by proteasomes. We propose that proteasome-mediated control of the intracellular levels of transcriptional activators could play an imp ortant role in the regulation of gene expression.