Mechanical Regulation of the Proangiogenic Factor CCN1/CYR61 Gene Requires the Combined Activities of MRTF-A and CREB-binding Protein Histone Acetyltransferase
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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 RhoA activation, actin remodeling, and recruitment of MRTF-A to the SRE of the CCN1 promoter.
“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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RetractedAITKEN, K. J., Yadav, P., Sidler, M., Thanabalasingam, T., Ahmed, T., Aggarwal, P., Yip, S. T., Jeffrey, N., Jiang, J., Siebenaller, A. R., et al. (2023) · PLoS ONE · doi:10.1371/journal.pone.0287205 · Cited by 1 · see citing works
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Self-citation
- 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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