© 2001 American Heart Association, Inc.
Molecular Medicine |
Transforming Growth Factor-ß/Smads Signaling Induces Transcription of the Cell Type–Restricted Ankyrin Repeat Protein CARP Gene Through CAGA Motif in Vascular Smooth Muscle Cells
From the Second Department of Internal Medicine (H.K., T.T., Y.A., M. Kurabayashi), Gunma University School of Medicine, Maebashi, Gunma, Japan; First Department of Internal Medicine (S.-i.T.), Tottori University School of Medicine, Yonago, Tottori, Japan; Department of Biochemistry (M. Kawabata, K.M.), The Cancer Institute, Tokyo, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo, Japan; and Department of Cardiovascular Medicine (R.N.), University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Correspondence to Masahiko Kurabayashi, MD, PhD, Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-15 Showa-machi Maebashi, Gunma, 371-8511, Japan. E-mail mkuraba{at}med.gunma-u.ac.jp
Abstract—Transforming growth factor (TGF)-ß plays a major role in the development of vascular diseases. Despite the pleiotropic effects of TGF-ß on vascular smooth muscle cells (VSMCs), only a few genes have been characterized as direct targets of TGF-ß in VSMCs. Cardiac ankyrin repeat protein (CARP) has been thought to be expressed exclusively in the heart. In the present study, we showed that CARP is expressed in the vasculature after balloon injury and in cultured VSMCs in response to TGF-ß. Analysis of a half-life of the cytoplasmic CARP mRNA levels and the transient transfection of the CARP promoter/luciferase gene indicates that the regulation of CARP expression is increased by TGF-ß at the transcriptional level. Transfection of expression vectors encoding Smads significantly activated the CARP promoter/luciferase activity. Deletion analysis and site-specific mutagenesis of the CARP promoter indicate that TGF-ß response element is localized to CAGA motif at -108 bp relative to the transcription start site. Electrophoretic mobility shift assays showed that the binding activity to the CAGA motif was increased in nuclear extracts of cultured VSMCs by TGF-ß. Cells transfected with adenovirus vector expressing CARP showed a significant decrease in DNA synthesis. Overexpression of CARP enhanced the TGF-ß–mediated inhibition of the DNA synthesis. These data indicate that CARP is a downstream target of TGF-ß/Smad signaling in VSMCs and suggest a role of CARP in mediation of the inhibitory effects of TGF-ß on the proliferation of VSMCs.
Key Words: proteins • growth factors • cells • transcription • muscle, smooth
This article has been cited by other articles:
 |
|
 |
|
  M. Moulik, M. Vatta, S. H. Witt, A. M. Arola, R. T. Murphy, W. J. McKenna, A. M. Boriek, K. Oka, S. Labeit, N. E. Bowles, et al. ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene. J. Am. Coll. Cardiol., July 21, 2009; 54(4): 325 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Fu, A. Chang, L. Chang, K. Niessen, S. Eapen, A. Setiadi, and A. Karsan Differential Regulation of Transforming Growth Factor {beta} Signaling Pathways by Notch in Human Endothelial Cells J. Biol. Chem., July 17, 2009; 284(29): 19452 - 19462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, H. El-Sikhry, K. R. Chaudhary, S. N. Batchu, A. Shayeganpour, T. O. Jukar, J. A. Bradbury, J. P. Graves, L. M. DeGraff, P. Myers, et al. Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H37 - H46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-J. Wei, C.-J. Cui, Y.-X. Huang, X.-L. Zhang, H. Zhang, and S.-S. Hu Upregulated expression of cardiac ankyrin repeat protein in human failing hearts due to arrhythmogenic right ventricular cardiomyopathy Eur J Heart Fail, June 1, 2009; 11(6): 559 - 566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Liu, C. Zhang, J. B. Feng, Y. X. Zhao, X. P. Wang, J. M. Yang, M. X. Zhang, X. L. Wang, and Y. Zhang Cross Talk Among Smad, MAPK, and Integrin Signaling Pathways Enhances Adventitial Fibroblast Functions Activated by Transforming Growth Factor-{beta}1 and Inhibited by Gax Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 725 - 731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Lehti, M. Silvennoinen, R. Kivela, H. Kainulainen, and J. Komulainen Effects of streptozotocin-induced diabetes and physical training on gene expression of titin-based stretch-sensing complexes in mouse striated muscle Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E533 - E542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. F. Clem and B. J. Clark Association of the mSin3A-Histone Deacetylase 1/2 Corepressor Complex with the Mouse Steroidogenic Acute Regulatory Protein Gene Mol. Endocrinol., January 1, 2006; 20(1): 100 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-J. Han, J.-K. Chae, M.-J. Lee, K.-R. You, B.-H. Lee, and D.-G. Kim Involvement of GADD153 and Cardiac Ankyrin Repeat Protein in Hypoxia-induced Apoptosis of H9c2 Cells J. Biol. Chem., June 17, 2005; 280(24): 23122 - 23129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Park, L. Liu, I.-H. Kim, J.-H. Kim, K.-R. You, and D.-G. Kim Identification of the Genes Involved in Enhanced Fenretinide-Induced Apoptosis by Parthenolide in Human Hepatoma Cells Cancer Res., April 1, 2005; 65(7): 2804 - 2814. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Shi, B. Reitmaier, J. Regenbogen, R. M. Slowey, S. R. Opalenik, E. Wolf, A. Goppelt, and J. M. Davidson CARP, a Cardiac Ankyrin Repeat Protein, Is Up-Regulated during Wound Healing and Induces Angiogenesis in Experimental Granulation Tissue Am. J. Pathol., January 1, 2005; 166(1): 303 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Spin, S. Nallamshetty, R. Tabibiazar, E. A. Ashley, J. Y. King, M. Chen, P. S. Tsao, and T. Quertermous Transcriptional profiling of in vitro smooth muscle cell differentiation identifies specific patterns of gene and pathway activation Physiol Genomics, November 17, 2004; 19(3): 292 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-W. Chen, M. J. Hubal, E. P. Hoffman, P. D. Thompson, and P. M. Clarkson Molecular responses of human muscle to eccentric exercise J Appl Physiol, December 1, 2003; 95(6): 2485 - 2494. [Abstract] [Full Text]
|
|
|
|
 |
|
 O. Zolk, M. Marx, E. Jackel, A. El-Armouche, and T. Eschenhagen {beta}-Adrenergic stimulation induces cardiac ankyrin repeat protein expression: involvement of protein kinase A and calmodulin-dependent kinase Cardiovasc Res, September 1, 2003; 59(3): 563 - 572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Boengler, F. Pipp, B. Fernandez, T. Ziegelhoeffer, W. Schaper, and E. Deindl Arteriogenesis is associated with an induction of the cardiac ankyrin repeat protein (carp) Cardiovasc Res, September 1, 2003; 59(3): 573 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Srisuma, S. S. Biswal, W. A. Mitzner, S. J. Gallagher, K. H. Mai, and E. M. Wagner Identification of Genes Promoting Angiogenesis in Mouse Lung by Transcriptional Profiling Am. J. Respir. Cell Mol. Biol., August 1, 2003; 29(2): 172 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ikeda, N. Emoto, M. Matsuo, and M. Yokoyama Molecular Identification and Characterization of a Novel Nuclear Protein Whose Expression Is Up-regulated in Insulin-resistant Animals J. Biol. Chem., January 31, 2003; 278(6): 3514 - 3520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. de Waard, T. A.E. van Achterberg, N. J. Beauchamp, H. Pannekoek, and C. J.M. de Vries Cardiac Ankyrin Repeat Protein (CARP) Expression in Human and Murine Atherosclerotic Lesions: Activin Induces Carp in Smooth Muscle Cells Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 64 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.C. Weston, I. Haviv, and P.A.W. Rogers Microarray analysis of VEGF-responsive genes in myometrial endothelial cells Mol. Hum. Reprod., September 1, 2002; 8(9): 855 - 863. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Pokharel, S. Rasoul, A. J.M. Roks, R. E.W. van Leeuwen, M. J.A. van Luyn, L. E. Deelman, J. F. Smits, O. Carretero, W. H. van Gilst, and Y. M. Pinto N-Acetyl-Ser-Asp-Lys-Pro Inhibits Phosphorylation of Smad2 in Cardiac Fibroblasts Hypertension, August 1, 2002; 40(2): 155 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Topper Transforming Growth Factor-{beta} (TGF-{beta}) and Vascular Disease: CARP as a Putative TGF-{beta} Target Gene in the Vessel Wall Circ. Res., January 19, 2001; 88(1): 5 - 6. [Full Text] [PDF]
|
|