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Mechanical Regulation of the Proangiogenic Factor CCN1/CYR61 Gene Requires the Combined Activities of MRTF-A and CREB-binding Protein Histone Acetyltransferase
Open accessAbstract
Smooth muscle-rich tissues respond to mechanical overload by an adaptive hypertrophic growth combined with activation of angiogenesis, which potentiates their mechanical overload-bearing capabilities. Neovascularization is associated with mechanical strain-dependent induction of angiogenic factors such as CCN1, an immediate-early gene-encoded matricellular molecule critical for vascular development and repair. Here we have demonstrated that mechanical strain-dependent induction of the CCN1 gene involves signaling cascades through RhoA-mediated actin remodeling and the p38 stress-activated protein kinase (SAPK). Actin signaling controls serum response factor (SRF) activity via SRF interaction with the myocardin-related transcriptional activator (MRTF)-A and tethering to a single CArG box sequence within the CCN1 promoter. Such activity was abolished in mechanically stimulated mouse MRTF-A(-/-) cells or upon inhibition of CREB-binding protein (CBP) histone acetyltransferase (HAT) either pharmacologically or by siRNAs. Mechanical strain induced CBP-mediated acetylation of histones 3 and 4 at the SRF-binding site and within the CCN1 gene coding region. Inhibition of p38 SAPK reduced CBP HAT activity and its recruitment to the SRF.MRTF-A complex, whereas enforced induction of p38 by upstream activators (e.g. MKK3 and MKK6) enhanced both CBP HAT and CCN1 promoter activities. Similarly, mechanical overload-induced CCN1 gene expression in vivo was associated with nuclear localization of MRTF-A and enrichment of the CCN1 promoter with both MRTF-A and acetylated histone H3. Taken together, these data suggest that signal-controlled activation of SRF, MRTF-A, and CBP provides a novel connection between mechanical stimuli and angiogenic gene expression.
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“Mechanical stretch induction of CCN1 in human smooth muscle cells involves activation of the RhoA GTPase, which promotes actin remodeling and consequently recruitment of the transcription factor myocardin-related transcriptional activator (MRTF-A), a G-actin-binding SRF co-activator, to the SRE of the CCN1 promoter [41].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [41]
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Metadata
- Authors
- Hanna, M., Liu, H., Amir, J., Sun, Y., Morris, S. W., Siddiqui, M. A. Q., Lau, L. F., & Chaqour, B.
- Affiliations
- SUNY Downstate Health Sciences University (US)
- St. Jude Children's Research Hospital (US)
- University of Illinois Chicago (US)
- Corresponding author
- Chaqour, Brahim
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 284
- Issue
- 34
- Pages
- 23125-23136
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2755718
- OpenAlex
- W2042134391
- Cited by
- 106
- References
- 58
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 3 · 2020: 8 · 2019: 5 · 2018: 3 · 2017: 9 · 2016: 4 · 2015: 14 · 2014: 14 · 2013: 11 · 2012: 3
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- St. Jude Children's Research Hospital
- American Lebanese Syrian Associated Charities
- National Institutes of Health
- National Cancer Institute (R01CA087064)
- National Institute of Diabetes and Digestive and Kidney Diseases (R21DK068483, R56DK060572)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- MRTF-A, CREB-binding protein, histone acetylation, mechanical strain, angiogenesis, smooth muscle hypertrophy, mechanical overload, serum response factor, p38 MAPK, RhoA signaling, actin cytoskeleton remodeling, CArG box, transcriptional regulation, histone H3 acetylation
- MeSH terms
- Acetylation, Animals, Base Sequence, Cells, Cultured, DNA-Binding Proteins, Enzyme Inhibitors, Histones, Humans, Immunohistochemistry, Molecular Sequence Data, Promoter Regions, Genetic, Protein Binding, Stress, Mechanical, Blotting, Western, Oncogene Proteins, Fusion, Trans-Activators, Protein Transport, Serum Response Element, Chromatin Immunoprecipitation, Immunoprecipitation, p38 Mitogen-Activated Protein Kinases, CREB-Binding Protein, Mice, Histone Acetyltransferases, Cysteine-Rich Protein 61
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