Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase.
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.
Hanna
Mary
M
Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
Liu
Haibo
H
Amir
Jawaria
J
Sun
Yi
Y
Morris
Stephan W
SW
Siddiqui
M A Q
MA
Lau
Lester F
LF
Chaqour
Brahim
B
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D055515:Cysteine-Rich Protein 61 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D027602:Serum Response Element / Q000235:genetics; D013314:Stress, Mechanical; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006657:Histones; C431575:MRTFA protein, human; C511173:Mrtfa protein, mouse; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; D048051:p38 Mitogen-Activated Protein Kinases