Transcriptional activity of Serum Response Factor is mediated by the RhoA/Rho kinase pathway during HSC differentiation and influences expression of Smooth Muscle Cell marker genes

2008 ◽  
Vol 46 (01) ◽  
Author(s):  
J Herrmann ◽  
U Haas ◽  
AM Gressner ◽  
R Weiskirchen
Keyword(s):  
Smooth Muscle ◽  
Transcriptional Activity ◽  
Serum Response Factor ◽  
Rho Kinase ◽  
Marker Genes ◽  
Response Factor ◽  
Cell Marker ◽  
Serum Response ◽  
Smooth Muscle Cell Marker ◽  
Kinase Pathway

2007 Russell Ross Memorial Lectureship in Vascular Biology—Epigenetic Control of Vascular Smooth Muscle Differentiation in Development and Disease

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Gary K. Owens
Keyword(s):  
Smooth Muscle ◽  
Vascular Injury ◽  
Serum Response Factor ◽  
Critical Role ◽  
Conditional Knockout ◽  
Phenotypic Switching ◽  
Marker Genes ◽  
List Type ◽  
Response Factor ◽  
Serum Response

There is clear evidence that alterations in the differentiated state of the smooth muscle cell (SMC) play a key role in the pathogenesis of a number of major human diseases, including atherosclerosis and postan-gioplasty restenosis. This process is referred to as “phenotypic switching” and likely evolved to promote repair of vascular injury. However, the mechanisms controlling phenotypic switching as well as normal differentiation of SMCs in vivo are poorly understood. This talk will provide an overview of molecular mechanisms that control differentiation of SMCs during vascular development. A particular focus will be to consider the role of CArG elements found within the promoters of many SMC differentiation marker genes, as well as regulation of their activity by serum response factor and the potent SMC-selective serum response factor coactivator myocardin. In addition, I will summarize recent work in our laboratory showing that SMC- and gene-locus–selective changes in chromatin structure play a critical role both in normal control of SMC differentiation and in phenotypic switching in response to vascular injury. Finally, I will present evidence based on conditional knockout experiments in mice showing that krupple-like factor 4 is induced in SMCs after vascular injury and regulates SMC phenotypic switching and growth through: binding to G/C repressor elements located in close proximity of CArG elements within the promoters of many SMC marker genes, suppressing expression of myocardin, and inducing epigenetic modifications of SMC marker gene loci associated with chromatin condensation and transcriptional silencing. Supported by NIH grants P01 HL19242, R37 HL57353, and R01 HL 38854.

scholarly journals The RhoA/Rho Kinase Pathway Regulates Nuclear Localization of Serum Response Factor

2003 ◽  
Vol 29 (1) ◽  
pp. 39-47 ◽  
Author(s):  
Hong Wei Liu ◽  
Andrew J. Halayko ◽  
Darren J. Fernandes ◽  
Gregory S. Harmon ◽  
Joel A. McCauley ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Serum Response Factor ◽  
Rho Kinase ◽  
Response Factor ◽  
Serum Response ◽  
Kinase Pathway

scholarly journals Enhancement of mDia2 activity by Rho-kinase-dependent phosphorylation of the diaphanous autoregulatory domain

2011 ◽  
Vol 439 (1) ◽  
pp. 57-65 ◽  
Author(s):  
Dean P. Staus ◽  
Joan M. Taylor ◽  
Christopher P. Mack
Keyword(s):  
Smooth Muscle ◽  
Actin Polymerization ◽  
Serum Response Factor ◽  
Rho Kinase ◽  
Specific Gene ◽  
Related Transcription Factor ◽  
Inhibitory Domain ◽  
Serum Response ◽  
Acidic Region ◽  
Basic Region

It is clear that RhoA activates the DRF (diaphanous-related formin) mDia2 by disrupting the molecular interaction between the DAD (diaphanous autoregulatory domain) and the DID (diaphanous inhibitory domain). Previous studies indicate that a basic motif within the DAD contributes to mDia2 auto-inhibition, and results shown in the present study suggest these residues bind a conserved acidic region within the DID. Furthermore, we demonstrate that mDia2 is phosphorylated by ROCK (Rho-kinase) at two conserved residues (Thr1061 and Ser1070) just C-terminal to the DAD basic region. Phosphomimetic mutations to these residues in the context of the full-length molecule enhanced mDia2 activity as measured by increased actin polymerization, SRF (serum response factor)-dependent smooth muscle-specific gene transcription, and nuclear localization of myocardin-related transcription factor B. Biochemical and functional data indicate that the T1061E/S1070E mutation significantly inhibited the ability of DAD to interact with DID and enhanced mDia2 activation by RhoA. Taken together, the results of the present study indicate that ROCK-dependent phosphorylation of the mDia2 DAD is an important determinant of mDia2 activity and that this signalling mechanism affects actin polymerization and smooth muscle cell-specific gene expression.

scholarly journals Serum Response Factor-dependent Regulation of the Smooth Muscle Calponin Gene

2000 ◽  
Vol 275 (13) ◽  
pp. 9814-9822 ◽  
Author(s):  
Joseph M. Miano ◽  
Michael J. Carlson ◽  
Jeffrey A. Spencer ◽  
Ravi P. Misra
Keyword(s):  
Smooth Muscle ◽  
Serum Response Factor ◽  
Response Factor ◽  
Serum Response

scholarly journals NADPH oxidase 4 mediates TGF-β-induced smooth muscle α-actin via p38MAPK and serum response factor

2011 ◽  
Vol 50 (2) ◽  
pp. 354-362 ◽  
Author(s):  
Abel Martin-Garrido ◽  
David I. Brown ◽  
Alicia N. Lyle ◽  
Anna Dikalova ◽  
Bonnie Seidel-Rogol ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Nadph Oxidase ◽  
Serum Response Factor ◽  
Response Factor ◽  
Nadph Oxidase 4 ◽  
Serum Response

scholarly journals Four isoforms of serum response factor that increase or inhibit smooth-muscle-specific promoter activity

2000 ◽  
Vol 345 (3) ◽  
pp. 445-451 ◽  
Author(s):  
Paul R. KEMP ◽  
James C. METCALFE
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Serum Response Factor ◽  
Muscle Cells ◽  
Dominant Negative ◽  
C2c12 Cells ◽  
Specific Gene ◽  
Response Factor ◽  
Transactivation Domain ◽  
Serum Response

Serum response factor (SRF) is a key transcriptional activator of the c-fos gene and of muscle-specific gene expression. We have identified four forms of the SRF coding sequence, SRF-L (the previously identified form), SRF-M, SRF-S and SRF-I, that are produced by alternative splicing. The new forms of SRF lack regions of the C-terminal transactivation domain by splicing out of exon 5 (SRF-M), exons 4 and 5 (SRF-S) and exons 3, 4 and 5 (SRF-I). SRF-M is expressed at similar levels to SRF-L in differentiated vascular smooth-muscle cells and skeletal-muscle cells, whereas SRF-L is the predominant form in many other tissues. SRF-S expression is restricted to vascular smooth muscle and SRF-I expression is restricted to the embryo. Transfection of SRF-L and SRF-M into C2C12 cells showed that both forms are transactivators of the promoter of the smooth-muscle-specific gene SM22α, whereas SRF-I acted as a dominant negative form of SRF.

Sign in / Sign up

Export Citation Format

Share Document