tyrphostin-ag825 and afimoxifene

Silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) is a transcriptional corepressor that participates in diverse signaling pathways and human diseases. However, regulation of SMRT stability remains largely unexplored. We show that the peptidyl-prolyl isomerase Pin1 interacts with SMRT both in vitro and in mammalian cells. This interaction requires the WW domain of Pin1 and SMRT phosphorylation. Pin1 regulates SMRT protein stability, thereby affecting SMRT-dependent transcriptional repression. SMRT phosphorylation at multiple sites is required for Pin1 interaction, and these sites can be phosphorylated by Cdk2, which interacts with SMRT. Cdk2-mediated phosphorylation of SMRT is required for Pin1 binding and decreases SMRT stability, whereas mutation of these phosphorylation sites abrogates Pin1 binding and stabilizes SMRT. Finally, decreases in SMRT stability occur in response to the activation of Her2/Neu/ErbB2, and this receptor functions upstream of both Pin1 and Cdk2 in the signaling cascade that regulates SMRT stability and cellular response to tamoxifen.

Topics: Animals; Benzothiazoles; Cell Line; Cell Proliferation; Chlorocebus aethiops; Cyclin-Dependent Kinase 2; Cyclins; DNA-Binding Proteins; Gene Expression; Genes, myc; Humans; Mice; Models, Biological; Mutation; Neuregulin-1; NIMA-Interacting Peptidylprolyl Isomerase; Nuclear Receptor Co-Repressor 2; Peptide Fragments; Peptidylprolyl Isomerase; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Receptor, ErbB-2; Receptors, Progesterone; Repressor Proteins; Signal Transduction; Tamoxifen; Two-Hybrid System Techniques; Tyrphostins