Certain steroid hormone receptors undergo ligand-induced degradation via the proteasome. Lonard et al. provide intriguing evidence that the proteasome is important both for degrading the estrogen-bound estrogen receptor α (ERα) and for promoting the transcriptional activity of these activated receptors. Disruption of proteasome activity, either with inhibitors or in cells with a temperature-sensitive mutation in the ubiquitin-activating enzyme UBA, resulted in stabilization of ERα and inhibition of estrogen-stimulated transcriptional activation of reporter genes. Analysis of mutant estrogen receptors indicated that the ability of the proteasome to regulate ERα activity and to promote ERα degradation was dependent on the receptor's interaction with coactivators, but not on DNA binding. The coactivators were also targets for proteasome-mediated degradation. Thus, the ability of the proteasome to stimulate ERα transcriptional activity may be by influencing the ER-coactivator interaction.
Lonard, D.M., Nawaz, Z., Smith, C.L., O'Malley, B.W. (2000) The 26S proteasome is required for estrogen receptor-α and coactivator turnover and for efficient estrogen receptor-α transactivation. Mol. Cell 5: 939-948. [Online Journal]