| Summary: | 碩士 === 國立中山大學 === 生物科學系研究所 === 106 === Transforming Growth Factor-β (TGF-β) is a multifunctional cytokine that involved in many biological processes. TGF-β signaling transduction initiates when binding to Type II TGF-β receptor (TβRII). Once binding to TGF-β, TβRII forms heterocomplex with Type I TGF-β receptor (TβRI) and phosphorylates Smad2 and Smad3. P-Smad2/3 then forms a homotrimer with Smad4. Finally, R-Smad/Smad4 complexes are then translocated into the nucleus where they act as a transcriptional regulator of target genes. TGF-β signaling plays an opposite role during carcinoma progression. In the early stage, TGF-β acts as a tumor suppressor through inhibiting cell proliferation. Conversely, TGF-β promotes tumor cell proliferation and enhances mobility of cell in the late stage of carcinoma. In addition, TGF-β also is associated to other diseases such as organ fibrosis and autoimmune diseases. Pentabromopseudilin (PBrP) is a natural chlorinated phenylpyrrole compound that shows a broad range of antimicrobial activity. In mammalian cells, PBrP acts as an allosteric inhibitor of myosin 1c (Myo1c). In this study, we find that PBrP attenuates TGF-β responsiveness by promoting degradation of surface TβRII. Furthermore, PBrP inhibits TGF-β-induced Smad2/3 phosphorylation and plasminogen activator inhibitor-1 (PAI-1) promoter activation with a IC50 betewwn 0.05 μM to 0.1μM. Abolishing the process of epithelial-to-mesenchymal transition (EMT) in A549 and HepG2 cells, PBrP is found to suppress the mobility of cells. The results also demonstrate that PBrP directs surface TβR-II translocation to non-raft fractions from lipid raft. The translocation is followed by internalization and degradation of TβRII via lysosomal pathway. By accelerating TβR-II degradation, PBrP inhibits TGF-β-stimulated cellular responsiveness.
|
|---|
