title: PKCδ as a regulator for TGF-β-stimulated connective tissue growth factor production in human hepatocarcinoma (HepG2) cells.
abstract: CTGF (connective tissue growth factor) is widely regarded as an important amplifier of the profibrogenic action of TGF-β (transforming growth factor β) in a variety of tissues, although the precise mechanism of how the TGF-β signalling pathways modulate CTGF expression remains unclear. In the present study, the role of PKCδ (protein kinase Cδ) in TGF-β1-mediated CTGF expression was investigated using HepG2 cells. TGF-β1 treatment specifically elevated PKCδ activation and CTGF expression. In contrast, blockade of PKCδ by the selective inhibitor Rottlerin or by siRNA knockdown significantly reduced TGF-β1-induced CTGF production. The regulatory mechanism was further demonstrated in HepG2 cells whereby TGF-β1-induced PKCδ activation negatively regulated the nuclear levels of PPM1A (protein phosphatase, Mg2+/Mn2+ dependent, 1A) through the RhoA/ROCK (Rho-associated kinase) pathway. Moreover, we showed that both Smad signalling and the PKCδ pathway appeared to be stimulated by TGF-β1 in parallel. Time course assessments indicated that PKCδ signalling may have a function in maintaining nuclear phospho-Smads at a maximal level. The collective results of the present study demonstrated that PKCδ-stimulated RhoA/ROCK activation resulted in a reduction in PPM1A, thereby up-regulating Smad-dependent gene induction for extended periods. These findings indicated that PKCδ plays a critical role in TGF-β1-induced CTGF production in HepG2 cells.
authors.affiliation: *School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, 702-701 Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jeong Han
authors.initials: JH
authors.lastname: Kang
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Oh-Shin
authors.initials: OS
authors.lastname: Kwon
mesh_terms: D055513:Connective Tissue Growth Factor / Q000096:biosynthesis*; D004789:Enzyme Activation; D056945:Hep G2 Cells; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D054460:rho-Associated Kinases; D051745:Protein Kinase C-delta; C000607456:PPM1A protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D020742:rhoA GTP-Binding Protein