HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 285/3/F413    most recent 00082.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (34) Citing Articles via Google Scholar Google Scholar Articles by Runyan, C. E. Articles by Poncelet, A.-C. Search for Related Content PubMed PubMed Citation Articles by Runyan, C. E. Articles by Poncelet, A.-C.

Smad3 and PKC mediate TGF-₁-induced collagen I expression in human mesangial cells

Department of Pediatrics, Northwestern University, Chicago, Illinois 60611

Submitted 25 February 2003 ; accepted in final form 14 May 2003

Transforming growth factor (TGF)- has been associated with fibrogenesis in clinical studies and animal models. We previously showed that Smad3 promotes COL1A2 gene activation by TGF-₁ in human mesangial cells. In addition to the Smad pathway, it has been suggested that TGF-₁ could also activate more classical growth factor signaling. Here, we report that protein kinase C (PKC) plays a role in TGF-₁-stimulated collagen I production. In an in vitro kinase assay, TGF-₁ treatment specifically increased mesangial cell PKC activity in a time-dependent manner. Translocation to the membrane was detected by immunocytochemistry and immunoblot, suggesting activation of PKC by TGF-₁. Inhibition of PKC by rottlerin decreased basal and TGF-₁-stimulated collagen I production, mRNA expression, and COL1A2 promoter activity, whereas blockade of conventional PKCs by Gö 6976 had little or no effect. In a Gal4-LUC assay system, inhibition of PKC abolished TGF-₁-induced transcriptional activity of Gal4-Smad3 and Gal4-Smad4(266-552). Overexpression of Smad3 or Smad3D, in which the three COOH-terminal serine phosphoacceptor residues have been mutated, increased activity of the SBE-LUC construct, containing four DNA binding sites for Smad3 and Smad4. This induction was blocked by PKC inhibition, suggesting that rottlerin decreased Smad3 transcriptional activity independently of COOH-terminal serine phosphorylation. Blockade of PKC abolished ligand-independent and ligand-dependent stimulation of COL1A2 promoter activity by Smad3. These data indicate that PKC is activated by TGF-₁ in human mesangial cells. TGF-₁-stimulated PKC activity positively regulates Smad transcriptional activity and is required for COL1A2 gene transcription. Thus cross talk among multiple signaling pathways likely contributes to the pathogenesis of glomerular matrix accumulation.

transforming growth factor- signal transduction; cross talk; gene regulation; extracellular matrix accumulation; glomerulosclerosis

This article has been cited by other articles:

				G. Elberg, L. Chen, D. Elberg, M. D. Chan, C. J. Logan, and M. A. Turman MKL1 mediates TGF-{beta}1-induced {alpha}-smooth muscle actin expression in human renal epithelial cells Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1116 - F1128. [Abstract] [Full Text] [PDF]

				H. J. Lee, Y. Ji, S. Paul, H. Maehr, M. Uskokovic, and N. Suh Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase C{alpha} Cancer Res., December 15, 2007; 67(24): 11840 - 11847. [Abstract] [Full Text] [PDF]

				J. Villar, M. I. Arenas, C. M. MacCarthy, M. J. Blanquez, O. M. Tirado, and V. Notario PCPH/ENTPD5 Expression Enhances the Invasiveness of Human Prostate Cancer Cells by a Protein Kinase C{delta} Dependent Mechanism Cancer Res., November 15, 2007; 67(22): 10859 - 10868. [Abstract] [Full Text] [PDF]

				B. Wang, A. Omar, T. Angelovska, V. Drobic, S. G. Rattan, S. C. Jones, and I. M. C. Dixon Regulation of collagen synthesis by inhibitory Smad7 in cardiac myofibroblasts Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1282 - H1290. [Abstract] [Full Text] [PDF]

				S. I. Kim, J. H. Kwak, M. Zachariah, Y. He, L. Wang, and M. E. Choi TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1471 - F1478. [Abstract] [Full Text] [PDF]

				M. Meier, J. Menne, J.-K. Park, M. Holtz, F. Gueler, T. Kirsch, M. Schiffer, M. Mengel, C. Lindschau, M. Leitges, et al. Deletion of Protein Kinase C-{varepsilon} Signaling Pathway Induces Glomerulosclerosis and Tubulointerstitial Fibrosis In Vivo J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1190 - 1198. [Abstract] [Full Text] [PDF]

				R. Mishra, L. Zhu, R. L. Eckert, and M. S. Simonson TGF-beta-regulated collagen type I accumulation: role of Src-based signals Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1361 - C1369. [Abstract] [Full Text] [PDF]

				M. C. Banas, W. T. Parks, K. L. Hudkins, B. Banas, M. Holdren, M. Iyoda, T. A. Wietecha, J. Kowalewska, G. Liu, and C. E. Alpers Localization of TGF-{beta} Signaling Intermediates Smad2, 3, 4, and 7 in Developing and Mature Human and Mouse Kidney J. Histochem. Cytochem., March 1, 2007; 55(3): 275 - 285. [Abstract] [Full Text] [PDF]

				E. J. Ryer, R. P. Hom, K. Sakakibara, K. I. Nakayama, K. Nakayama, P. L. Faries, B. Liu, and K. C. Kent PKC{delta} Is Necessary for Smad3 Expression and Transforming Growth Factor {beta}-Induced Fibronectin Synthesis in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 780 - 786. [Abstract] [Full Text] [PDF]

				M.-S. Lee, T. Y. Kim, Y.-B. Kim, S.-Y. Lee, S.-G. Ko, H.-S. Jong, T.-Y. Kim, Y.-J. Bang, and J. W. Lee The Signaling Network of Transforming Growth Factor {beta}1, Protein Kinase C{delta}, and Integrin Underlies the Spreading and Invasiveness of Gastric Carcinoma Cells Mol. Cell. Biol., August 15, 2005; 25(16): 6921 - 6936. [Abstract] [Full Text] [PDF]

				C. E. Runyan, H. W. Schnaper, and A.-C. Poncelet The Role of Internalization in Transforming Growth Factor {beta}1-induced Smad2 Association with Smad Anchor for Receptor Activation (SARA) and Smad2-dependent Signaling in Human Mesangial Cells J. Biol. Chem., March 4, 2005; 280(9): 8300 - 8308. [Abstract] [Full Text] [PDF]

				Y.-S. Kim, Z.-G. Xu, M. A. Reddy, S.-L. Li, L. Lanting, K. Sharma, S. G. Adler, and R. Natarajan Novel Interactions between TGF-{beta}1 Actions and the 12/15-Lipoxygenase Pathway in Mesangial Cells J. Am. Soc. Nephrol., February 1, 2005; 16(2): 352 - 362. [Abstract] [Full Text] [PDF]

				S.S. Prime, M. Pring, M. Davies, and I.C. Paterson TGF-{beta} SIGNAL TRANSDUCTION IN ORO-FACIAL HEALTH AND NON-MALIGNANT DISEASE (PART I) Crit. Rev. Oral. Biol. Med., November 1, 2004; 15(6): 324 - 336. [Abstract] [Full Text] [PDF]

				V. Chintalgattu and L. C. Katwa Role of Protein Kinase C{delta} in Endothelin-Induced Type I Collagen Expression in Cardiac Myofibroblasts Isolated from the Site of Myocardial Infarction J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 691 - 699. [Abstract] [Full Text] [PDF]

				S. Rosenkranz TGF-{beta}1 and angiotensin networking in cardiac remodeling Cardiovasc Res, August 15, 2004; 63(3): 423 - 432. [Abstract] [Full Text] [PDF]

				T. Hayashida and H. W. Schnaper High Ambient Glucose Enhances Sensitivity to TGF-{beta}1 via Extracellular Signal--Regulated Kinase and Protein Kinase C{delta} Activities in Human Mesangial Cells J. Am. Soc. Nephrol., August 1, 2004; 15(8): 2032 - 2041. [Abstract] [Full Text] [PDF]

				C. E. Runyan, H. W. Schnaper, and A.-C. Poncelet The Phosphatidylinositol 3-Kinase/Akt Pathway Enhances Smad3-stimulated Mesangial Cell Collagen I Expression in Response to Transforming Growth Factor-{beta}1 J. Biol. Chem., January 23, 2004; 279(4): 2632 - 2639. [Abstract] [Full Text] [PDF]