Circulation Research. 2003;92:856-864
Published online before print March 27, 2003, doi: 10.1161/01.RES.0000068405.49081.09
Published online before print March 27, 2003, doi: 10.1161/01.RES.0000068405.49081.09
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2003 American Heart Association, Inc.
Molecular Medicine |
Myocardin Is a Key Regulator of CArG-Dependent Transcription of Multiple Smooth Muscle Marker Genes
From the Departments of Molecular Physiology and Biological Physics (T.Y., S.S., F.D., B.R.W., M.H.H., G.K.O.) and Microbiology (B.E.K.), University of Virginia, Charlottesville, Va; and the Department of Molecular Biology (D.-Z.W., E.N.O.), University of Texas Southwestern Medical Center, Dallas, Tex.
Correspondence to Gary K. Owens, PhD, Department of Molecular Physiology and Biological Physics, University of Virginia, PO Box 800736, Charlottesville, VA 22908-0736. E-mail gko{at}virginia.edu
The interactions between serum response factor (SRF) and CArG elements are critical for smooth muscle cell (SMC) marker gene transcription. However, the mechanisms whereby SRF, which is expressed ubiquitously, contributes to SMC-specific transcription are unknown. Myocardin was recently cloned as a coactivator of SRF in the heart, but its role in regulating CArG-dependent expression of SMC differentiation marker genes has not been clearly elucidated. In this study, we examined the expression and the function of myocardin in SMCs. In adult mice, myocardin mRNA was expressed in multiple smooth muscle (SM) tissues including the aorta, bladder, stomach, intestine, and colon, as well as the heart. Myocardin was also expressed in cultured rat aortic SMCs and A404 SMC precursor cells. Of particular interest, expression of myocardin was induced during differentiation of A404 cells, although it was not expressed in parental P19 cells from which A404 cells were derived. Cotransfection studies in SMCs revealed that myocardin induced the activity of multiple SMC marker gene promoters including SM 
-actin, SM-myosin heavy chain, and SM22 by 9- to 60-fold in a CArG-dependent manner, whereas myocardin short interfering RNA markedly decreased activity of these promoters. Moreover, adenovirus-mediated overexpression of a dominant-negative form of myocardin significantly suppressed expression of endogenous SMC marker genes, whereas adenovirus-mediated overexpression of wild-type myocardin increased expression. Taken together, results provide compelling evidence that myocardin plays a key role as a transcriptional coactivator of SMC marker genes through CArG-dependent mechanisms.
Key Words: smooth muscle cells • transcriptional coactivator • serum response factor • CArG element
This article has been cited by other articles:
 |
|
 |
|
  M. S. Parmacek Myocardin: Dominant Driver of the Smooth Muscle Cell Contractile Phenotype Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1416 - 1417. [Full Text] [PDF]
|
|
|
|
|
|
X. Long, R. D. Bell, W. T. Gerthoffer, B. V. Zlokovic, and J. M. Miano Myocardin Is Sufficient for a Smooth Muscle-Like Contractile Phenotype Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1505 - 1510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R. Wamhoff, K. R. Lynch, T. L. Macdonald, and G. K. Owens Sphingosine-1-Phosphate Receptor Subtypes Differentially Regulate Smooth Muscle Cell Phenotype Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1454 - 1461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.L. Tharp, B.R. Wamhoff, H. Wulff, G. Raman, A. Cheong, and D.K. Bowles Local Delivery of the KCa3.1 Blocker, TRAM-34, Prevents Acute Angioplasty-Induced Coronary Smooth Muscle Phenotypic Modulation and Limits Stenosis Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1084 - 1089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-W. Lin, I.-C. Chang, A. Tseng, M.-L. Wu, C.-H. Chen, C. A. Patenaude, M. D. Layne, and S.-F. Yet Transforming Growth Factor {beta} Up-regulates Cysteine-rich Protein 2 in Vascular Smooth Muscle Cells via Activating Transcription Factor 2 J. Biol. Chem., May 30, 2008; 283(22): 15003 - 15014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Shang, T. Yoshida, B. A. Amendt, J. F. Martin, and G. K. Owens Pitx2 is functionally important in the early stages of vascular smooth muscle cell differentiation J. Cell Biol., May 1, 2008; 181(3): 461 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 P. Au, J. Tam, D. Fukumura, and R. K. Jain Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature Blood, May 1, 2008; 111(9): 4551 - 4558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kennard, H. Liu, and B. Lilly Transforming Growth Factor- (TGF- 1) Down-regulates Notch3 in Fibroblasts to Promote Smooth Muscle Gene Expression J. Biol. Chem., January 18, 2008; 283(3): 1324 - 1333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Zhang, S. Zhuang, D. E. Casteel, D. J. Looney, G. R. Boss, and R. B. Pilz A Cysteine-rich LIM-only Protein Mediates Regulation of Smooth Muscle-specific Gene Expression by cGMP-dependent Protein Kinase J. Biol. Chem., November 16, 2007; 282(46): 33367 - 33380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Gan, T. Yoshida, J. Li, and G. K. Owens Smooth Muscle Cells and Myofibroblasts Use Distinct Transcriptional Mechanisms for Smooth Muscle {alpha}-Actin Expression Circ. Res., October 26, 2007; 101(9): 883 - 892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Pidkovka, O. A. Cherepanova, T. Yoshida, M. R. Alexander, R. A. Deaton, J. A. Thomas, N. Leitinger, and G. K. Owens Oxidized Phospholipids Induce Phenotypic Switching of Vascular Smooth Muscle Cells In Vivo and In Vitro Circ. Res., October 12, 2007; 101(8): 792 - 801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kanematsu, A. Ramachandran, and R. M. Adam GATA-6 mediates human bladder smooth muscle differentiation: involvement of a novel enhancer element in regulating {alpha}-smooth muscle actin gene expression Am J Physiol Cell Physiol, September 1, 2007; 293(3): C1093 - C1102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zhang, H. Fang, J. Zhou, and B. P. Herring A Novel Role of Brg1 in the Regulation of SRF/MRTFA-dependent Smooth Muscle-specific Gene Expression J. Biol. Chem., August 31, 2007; 282(35): 25708 - 25716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Li, Z. Luo, W. Huang, Q. Lu, C. S. Wilcox, P. A. Jose, and S. Chen Response Gene to Complement 32, a Novel Regulator for Transforming Growth Factor-beta-induced Smooth Muscle Differentiation of Neural Crest Cells J. Biol. Chem., April 6, 2007; 282(14): 10133 - 10137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Parmacek Myocardin-Related Transcription Factors: Critical Coactivators Regulating Cardiovascular Development and Adaptation Circ. Res., March 16, 2007; 100(5): 633 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Staus, A. L. Blaker, J. M. Taylor, and C. P. Mack Diaphanous 1 and 2 Regulate Smooth Muscle Cell Differentiation by Activating the Myocardin-Related Transcription Factors Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 478 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Touw, A. M. Hoggatt, G. Simon, and B. P. Herring Hprt-targeted transgenes provide new insights into smooth muscle-restricted promoter activity Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1024 - C1032. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yoshida, Q. Gan, Y. Shang, and G. K. Owens Platelet-derived growth factor-BB represses smooth muscle cell marker genes via changes in binding of MKL factors and histone deacetylases to their promoters Am J Physiol Cell Physiol, February 1, 2007; 292(2): C886 - C895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Chow, R. D. Bell, R. Deane, J. W. Streb, J. Chen, A. Brooks, W. Van Nostrand, J. M. Miano, and B. V. Zlokovic Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype PNAS, January 16, 2007; 104(3): 823 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kawai-Kowase and G. K. Owens Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells Am J Physiol Cell Physiol, January 1, 2007; 292(1): C59 - C69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Jeon, H. J. Moon, M. J. Lee, H. Y. Song, Y. M. Kim, Y. C. Bae, J. S. Jung, and J. H. Kim Sphingosylphosphorylcholine induces differentiation of human mesenchymal stem cells into smooth-muscle-like cells through a TGF-{beta}-dependent mechanism J. Cell Sci., December 1, 2006; 119(23): 4994 - 5005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. Herring, O. El-Mounayri, P. J. Gallagher, F. Yin, and J. Zhou Regulation of myosin light chain kinase and telokin expression in smooth muscle tissues Am J Physiol Cell Physiol, November 1, 2006; 291(5): C817 - C827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. E. Creemers, L. B. Sutherland, J. McAnally, J. A. Richardson, and E. N. Olson Myocardin is a direct transcriptional target of Mef2, Tead and Foxo proteins during cardiovascular development Development, November 1, 2006; 133(21): 4245 - 4256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Tharp, B. R. Wamhoff, J. R. Turk, and D. K. Bowles Upregulation of intermediate-conductance Ca2+-activated K+ channel (IKCa1) mediates phenotypic modulation of coronary smooth muscle Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2493 - H2503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Doi, T. Iso, H. Sato, M. Yamazaki, H. Matsui, T. Tanaka, I. Manabe, M. Arai, R. Nagai, and M. Kurabayashi Jagged1-selective Notch Signaling Induces Smooth Muscle Differentiation via a RBP-J{kappa}-dependent Pathway J. Biol. Chem., September 29, 2006; 281(39): 28555 - 28564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Li, S. Chang, X. Qi, J. A. Richardson, and E. N. Olson Requirement of a Myocardin-Related Transcription Factor for Development of Mammary Myoepithelial Cells Mol. Cell. Biol., August 1, 2006; 26(15): 5797 - 5808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun, K. Boyd, W. Xu, J. Ma, C. W. Jackson, A. Fu, J. M. Shillingford, G. W. Robinson, L. Hennighausen, J. K. Hitzler, et al. Acute Myeloid Leukemia-Associated Mkl1 (Mrtf-a) Is a Key Regulator of Mammary Gland Function Mol. Cell. Biol., August 1, 2006; 26(15): 5809 - 5826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sinha, B. R. Wamhoff, M. H. Hoofnagle, J. Thomas, R. L. Neppl, T. Deering, B. P. Helmke, D. K. Bowles, A. V. Somlyo, and G. K. Owens Assessment of Contractility of Purified Smooth Muscle Cells Derived from Embryonic Stem Cells Stem Cells, July 1, 2006; 24(7): 1678 - 1688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Yin, A. M. Hoggatt, J. Zhou, and B. P. Herring 130-kDa smooth muscle myosin light chain kinase is transcribed from a CArG-dependent, internal promoter within the mouse mylk gene Am J Physiol Cell Physiol, June 1, 2006; 290(6): C1599 - C1609. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Xing, T.-C. Zhang, D. Cao, Z. Wang, C. L. Antos, S. Li, Y. Wang, E. N. Olson, and D.-Z. Wang Myocardin Induces Cardiomyocyte Hypertrophy Circ. Res., April 28, 2006; 98(8): 1089 - 1097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R. Wamhoff, D. K. Bowles, and G. K. Owens Excitation-Transcription Coupling in Arterial Smooth Muscle Circ. Res., April 14, 2006; 98(7): 868 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S.M. Rensen, P. M.G. Niessen, X. Long, P. A. Doevendans, J. M. Miano, and G. J.J.M. van Eys Contribution of serum response factor and myocardin to transcriptional regulation of smoothelins Cardiovasc Res, April 1, 2006; 70(1): 136 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Gorenne, L. Jin, T. Yoshida, J.M. Sanders, I.J. Sarembock, G.K. Owens, A.P. Somlyo, and A.V. Somlyo LPP Expression During In Vitro Smooth Muscle Differentiation and Stent-Induced Vascular Injury Circ. Res., February 17, 2006; 98(3): 378 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhou, G. Hu, and B. P. Herring Smooth Muscle-Specific Genes Are Differentially Sensitive to Inhibition by Elk-1 Mol. Cell. Biol., November 15, 2005; 25(22): 9874 - 9885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Callis, D. Cao, and D.-Z. Wang Bone Morphogenetic Protein Signaling Modulates Myocardin Transactivation of Cardiac Genes Circ. Res., November 11, 2005; 97(10): 992 - 1000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Qiu, R. P. Ritchie, Z. Fu, D. Cao, J. Cumming, J. M. Miano, D.-Z. Wang, H. J. Li, and L. Li Myocardin Enhances Smad3-Mediated Transforming Growth Factor-{beta}1 Signaling in a CArG Box-Independent Manner: Smad-Binding Element Is an Important cis Element for SM22{alpha} Transcription In Vivo Circ. Res., November 11, 2005; 97(10): 983 - 991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Doi, T. Iso, M. Yamazaki, H. Akiyama, H. Kanai, H. Sato, K. Kawai-Kowase, T. Tanaka, T. Maeno, E.-i. Okamoto, et al. HERP1 Inhibits Myocardin-Induced Vascular Smooth Muscle Cell Differentiation by Interfering With SRF Binding to CArG Box Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2328 - 2334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Francis, S. K. Chakrabarti, J. C. Garmey, and R. G. Mirmira Pdx-1 Links Histone H3-Lys-4 Methylation to RNA Polymerase II Elongation during Activation of Insulin Transcription J. Biol. Chem., October 28, 2005; 280(43): 36244 - 36253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Oh, J. A. Richardson, and E. N. Olson Requirement of myocardin-related transcription factor-B for remodeling of branchial arch arteries and smooth muscle differentiation PNAS, October 18, 2005; 102(42): 15122 - 15127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kawai-Kowase, M. S. Kumar, M. H. Hoofnagle, T. Yoshida, and G. K. Owens PIAS1 Activates the Expression of Smooth Muscle Cell Differentiation Marker Genes by Interacting with Serum Response Factor and Class I Basic Helix-Loop-Helix Proteins Mol. Cell. Biol., September 15, 2005; 25(18): 8009 - 8023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. van Tuyn, S. Knaan-Shanzer, M. J.M. van de Watering, M. de Graaf, A. van der Laarse, M. J. Schalij, E. E. van der Wall, A. A.F. de Vries, and D. E. Atsma Activation of cardiac and smooth muscle-specific genes in primary human cells after forced expression of human myocardin Cardiovasc Res, August 1, 2005; 67(2): 245 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. G. Bosc, J. J. Layne, M. T. Nelson, and D. C. Hill-Eubanks Nuclear Factor of Activated T Cells and Serum Response Factor Cooperatively Regulate the Activity of an {alpha}-Actin Intronic Enhancer J. Biol. Chem., July 15, 2005; 280(28): 26113 - 26120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhou and B. P. Herring Mechanisms Responsible for the Promoter-specific Effects of Myocardin J. Biol. Chem., March 18, 2005; 280(11): 10861 - 10869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Proweller, W. S. Pear, and M. S. Parmacek Notch Signaling Represses Myocardin-induced Smooth Muscle Cell Differentiation J. Biol. Chem., March 11, 2005; 280(10): 8994 - 9004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu, S. Sinha, O. G. McDonald, Y. Shang, M. H. Hoofnagle, and G. K. Owens Kruppel-like Factor 4 Abrogates Myocardin-induced Activation of Smooth Muscle Gene Expression J. Biol. Chem., March 11, 2005; 280(10): 9719 - 9727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Small, A. S. Warkman, D.-Z. Wang, L. B. Sutherland, E. N. Olson, and P. A. Krieg Myocardin is sufficient and necessary for cardiac gene expression in Xenopus Development, March 1, 2005; 132(5): 987 - 997. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yoshida and G. K. Owens Molecular Determinants of Vascular Smooth Muscle Cell Diversity Circ. Res., February 18, 2005; 96(3): 280 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Streb and J. M. Miano AKAP12{alpha}, an Atypical Serum Response Factor-dependent Target Gene J. Biol. Chem., February 11, 2005; 280(6): 4125 - 4134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Yin and B. P. Herring GATA-6 Can Act as a Positive or Negative Regulator of Smooth Muscle-specific Gene Expression J. Biol. Chem., February 11, 2005; 280(6): 4745 - 4752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Drori, G. D. Girnun, L. Tou, J. D. Szwaya, E. Mueller, X. Kia, R. A. Shivdasani, and B. M. Spiegelman Hic-5 regulates an epithelial program mediated by PPAR{gamma} Genes & Dev., February 1, 2005; 19(3): 362 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Lepore, T. P. Cappola, P. A. Mericko, E. E. Morrisey, and M. S. Parmacek GATA-6 Regulates Genes Promoting Synthetic Functions in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 309 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Li, M. P. Czubryt, J. McAnally, R. Bassel-Duby, J. A. Richardson, F. F. Wiebel, A. Nordheim, and E. N. Olson Requirement for serum response factor for skeletal muscle growth and maturation revealed by tissue-specific gene deletion in mice PNAS, January 25, 2005; 102(4): 1082 - 1087. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Cao, Z. Wang, C.-L. Zhang, J. Oh, W. Xing, S. Li, J. A. Richardson, D.-Z. Wang, and E. N. Olson Modulation of Smooth Muscle Gene Expression by Association of Histone Acetyltransferases and Deacetylases with Myocardin Mol. Cell. Biol., January 1, 2005; 25(1): 364 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Miano, N. Ramanan, M. A. Georger, K. L. de Mesy Bentley, R. L. Emerson, R. O. Balza Jr., Q. Xiao, H. Weiler, D. D. Ginty, and R. P. Misra Restricted inactivation of serum response factor to the cardiovascular system PNAS, December 7, 2004; 101(49): 17132 - 17137. [Abstract] [Full Text] [PDF]
|