Study of the Associated Proteins of STAT3 and Characterization of their Functions: Roles of GRIM-19 and PIN1 in the Regulation of STAT3 Activity

Abstract

Signal transducer and activator of transcription 3 (Stat3) is a latent cytoplasmic transcription factor activated by cytokines and growth factors. In this thesis, GRIM-19, a gene product related to interferon-beta- and retinoic acid-induced cancer cell death, was shown to interact with Stat3. GRIM-19 forms aggregates at the perinulear region with co-expressed Stat3, which inhibits Stat3 nuclear translocation. GRIM-19 represses Stat3 transcriptional activity and its target gene expression, and also suppresses cell growth in Src-transformed cells. In the second part of this thesis, peptidyl-prolyl isomerase Pin1 was demonstrated to interact with activated Stat3 via its phosphorylated Ser727-Pro motif upon ligand stimulation. Pin1 promotes Stat3 transcriptional activity and target gene expression, and is required for the optimal Stat3 DNA binding. Expression of Pin1 significantly increases the cytokine-induced Stat3-p300 interaction. In addition, Pin1 also protects activated Stat3 from ubiquitination. Our data suggest that GRIM-19 and Pin1 are novel Stat3-associated proteins that regulate its activity by distinct mechanisms.