Figure 1

Degradation of pathways for SMRT and N-CoR. SMRT and N-CoR are subject to unique degradation pathways. Estrogen (E2) increases mRNA levels of the E3 ubiquitin ligase mSiah2. mSiah2 targets N-CoR for degradation by the proteasome. SMRT is degraded by a distinct pathway. SMRT is phosphorylated by Cyclin-dependent kinase 2 (Cdk2) and potentially other kinases. Phosphorylated SMRT then serves as a substrate for the peptidyl-prolyl isomerase Pin1 which alters the conformation of its substrate. Both Pin1 levels and Cdk activity are increased by the oncoprotein ErbB2; furthermore, Pin1 can increase ErbB2 activity. SMRT is then degraded, likely by subsequent ubiquitination and targeting to the proteasome. Loss of corepressors likely increases transcription of target genes, including some involved in proliferation. Corepressor degradation also likely contributes to tamoxifen resistance.