Mechanical Regulation of the Proangiogenic Factor CCN1/CYR61 Gene Requires the Combined Activities of MRTF-A and CREB-binding Protein Histone Acetyltransferase

• Published in: The Journal of biological chemistry Vol. 284; no. 34; pp. 23125 - 23136
• Main Authors: Hanna, Mary, Liu, Haibo, Amir, Jawaria, Sun, Yi, Morris, Stephan W., Siddiqui, M.A.Q., Lau, Lester F., Chaqour, Brahim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.08.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation - drug effects; Animals; Base Sequence; Blotting, Western; Cells, Cultured; Chromatin Immunoprecipitation; CREB-Binding Protein - antagonists & inhibitors; CREB-Binding Protein - genetics; CREB-Binding Protein - physiology; Cysteine-Rich Protein 61 - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Enzyme Inhibitors - pharmacology; Histone Acetyltransferases - antagonists & inhibitors; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Histones - metabolism; Humans; Immunohistochemistry; Immunoprecipitation; Mice; Molecular Sequence Data; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncogene Proteins, Fusion - physiology; p38 Mitogen-Activated Protein Kinases - metabolism; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Protein Binding - genetics; Protein Transport - drug effects; Protein Transport - genetics; Serum Response Element - genetics; Stress, Mechanical; Trans-Activators - genetics; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription, Chromatin, and Epigenetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.019059

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.